Disubstituted pyrazolines and triazolines as factor Xa inhibitors

ABSTRACT

The present application describes disubstituted pyrazolines and triazolines of formulae I and II:  
                 
 
     or pharmaceutically acceptable salt forms thereof, wherein one of M 1  and M 2  maybe N and D may be a variety of N-containing groups, which are useful as inhibitors of factor Xa.

FIELD OF THE INVENTION

[0001] This invention relates generally to disubstituted pyrazolines and triazolines which are inhibitors of trypsin-like serine protease enzymes, especially factor Xa, pharmaceutical compositions containing the same, and methods of using the same as anticoagulant agents for treatment and prevention of thromboembolic disorders.

BACKGROUND OF THE INVENTION

[0002] WO 95/18111 addresses fibrinogen receptor antagonists, containing basic and acidic termini, of the formula:

[0003] wherein R¹ represents the basic termini, U is an alkylene or heteroatom linker, V may be a heterocycle, and the right hand portion of the molecule represents the acidic termini. The presently claimed compounds do not contain the acidic termini of WO 95/18111.

[0004] In U.S. Pat. No. 5,463,071, Himmelsbach et al depict cell aggregation inhibitors which are 5-membered heterocycles of the formula:

[0005] wherein the heterocycle may be aromatic and groups A—B—C— and F—E—D— are attached to the ring system. A—B—C— can be a wide variety of substituents including a basic group attached to an aromatic ring. The F—E—D— group, however, would appear to be an acidic functionality which differs from the present invention. Furthermore, use of these compounds as inhibitors of factor Xa is not discussed.

[0006] WO 97/47299 describes amidino and guanidino heterocyclic protease inhibitors of the formula:

R¹—Z—X—Y—W

[0007] wherein W contains an amidino, guanidino, or imino group attached to a variety of moieties including phenyl and piperidinyl, Y is a O, N, S, or C linker or is absent, X is a heterocycle, Z is a two atom linker containing at least one heteroatom, and R¹ is a variety of groups including cycloalkyl, aryl, heteroaryl, and araalkyl all of which are optionally substituted. A variety of proteases are described as possible targets for these compounds including Factor Xa. The presently claimed compounds differ in that they do not contain the combination R¹—Z or Y—W.

[0008] WO 97/23212 describes isoxazolines, isothiazolines, and pyrazolines of the formula:

[0009] wherein X is O, S or NR¹⁵. Though the pyrazolines of WO 97/23212 are indicated to be factor Xa inhibitors, they are not considered part of the present invention.

[0010] Activated factor Xa, whose major practical role is the generation of thrombin by the limited proteolysis of prothrombin, holds a central position that links the intrinsic and extrinsic activation mechanisms in the final common pathway of blood coagulation. The generation of thrombin, the final serine protease in the pathway to generate a fibrin clot, from its precursor is amplified by formation of prothrombinase complex (factor Xa, factor V, Ca²⁺ and phospholipid). Since it is calculated that one molecule of factor Xa can generate 138 molecules of thrombin (Elodi, S., Varadi, K.: Optimization of conditions for the catalytic effect of the factor IXa-factor VIII Complex: Probable role of the complex in the amplification of blood coagulation. Thromb. Res. 1979, 15, 617-629), inhibition of factor Xa may be more efficient than inactivation of thrombin in interrupting the blood coagulation system.

[0011] Therefore, efficacious and specific inhibitors of factor Xa are needed as potentially valuable therapeutic agents for the treatment of thromboembolic disorders. It is thus desirable to discover new factor Xa inhibitors.

SUMMARY OF THE INVENTION

[0012] Accordingly, one object of the present invention is to provide novel disubstituted pyrazolines and triazolines which are useful as factor Xa inhibitors or pharmaceutically acceptable salts or prodrugs thereof.

[0013] It is another object of the present invention to provide pharmaceutical compositions comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of at least one of the compounds of the present invention or a pharmaceutically acceptable salt or prodrug form thereof.

[0014] It is another object of the present invention to provide a method for treating thromboembolic disorders comprising administering to a host in need of such treatment a therapeutically effective amount of at least one of the compounds of the present invention or a pharmaceutically acceptable salt or prodrug form thereof.

[0015] These and other objects, which will become apparent during the following detailed description, have been achieved by the inventors' discovery that compounds of formulae I and II:

[0016] or pharmaceutically acceptable salt or prodrug forms thereof, wherein A, B, D, E, G, M, Z, R^(1a), R^(1b), and s are defined below, are effective factor Xa inhibitors.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

[0017] [1] Thus, in a first embodiment, the present invention provides novel compounds of formulae I or II:

[0018] or a stereoisomer or pharmaceutically acceptable salt thereof, wherein;

[0019] M¹ is N or CR^(1c);

[0020] M² is NR^(1a) or CR^(1a)R^(1a), provided that only one of M¹ and M² is a N atom;

[0021] D is selected from C(═NR⁸)NR⁷R⁹, NHC(═NR⁸)NR⁷R⁹, NR⁸CH(═NR⁷), C(O)NR⁷R⁸, and CR⁸R⁹NR⁷R⁸;

[0022] E is selected from phenyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, and piperidinyl substituted with 1 R;

[0023] alternatively, D—E—G together represent pyridyl substituted with 1 R;

[0024] R is selected from H, Cl, F, Br, I, (CH₂)_(t)OR³, C₁₋₄ alkyl, OCF₃, CF₃, C(O)NR⁷R⁸, and (CR⁸R⁹)_(t)NR⁷R⁸;

[0025] G is selected from NHCH₂, OCH₂, and SCH₂, provided that when s is 0, then G is absent;

[0026] z is selected from a C₁₋₄ alkylene, (CH₂)_(r)O(CH₂)_(r), (CH₂)_(r)NR³(CH₂)_(r), (CH₂)_(r)C(O)(CH₂)_(r), (CH₂)_(r)C(O)O(CH₂)_(r), (CH₂)_(r)OC(O)(CH₂)_(r), (CH₂)_(r)C(O)NR³(CH₂)_(r), (CH₂)_(r)NR³C(O)(CH₂)_(r), (CH₂)_(r)OC(O)O(CH₂)_(r), (CH₂)_(r)OC(O)NR³(CH₂)_(r), (CH₂)_(r)NR³C(O)O(CH₂)_(r), (CH₂)_(r)NR³C(O)NR³(CH₂)_(r), (CH₂)_(r)S(O)_(p)(CH₂)_(r), (CH₂)_(r)SO₂NR³(CH₂)_(r), (CH₂)_(r)NR³ SO₂(CH₂)_(r), and (CH₂)_(r)NR³SO₂NR³(CH₂)_(r), provided that Z does not form a N—N, N—O, N—S, NCH₂N, NCH₂O, or NCH₂S bond with group A;

[0027] R^(1a) and R^(1b) are, at each occurrence, independently selected from H, —(CH₂)_(r)—R¹′, NCH₂R¹″, OCH₂R¹″, SCH₂R¹″, N(CH₂)₂(CH₂)_(t)R¹′, O(CH₂)₂(CH₂)_(t)R¹′, and S(CH₂)₂(CH₂)_(t)R¹′;

[0028] R^(1c) is selected from H, —(CH₂)_(q)—R¹′, C₁₋₃ alkyl, C(O)R^(2c), (CF₂)_(r)CO₂R^(2c), C(O)NR²R^(2a), C₃₋₆ carbocyclic residue substituted with 0-2 R⁴, and 5-10 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R⁴;

[0029] R¹′ is selected from H, C₁₋₃ alkyl, halo, (CF₂)_(r)CF₃, OR², NR²R^(2a), C(O)R^(2c), OC(O)R², (CF₂)_(r)CO₂R^(2c), S(O)_(p)R^(2b), NR²(CH₂)_(r)OR², NR²C(O)R^(2b), NR²C(O)NHR^(2b), NR²C(O)₂R^(2a), OC(₀)NR^(2b), C(O)NR²R^(2a), SO₂NR²R^(2a), NR²SO₂R^(2b), C₃₋₆ carbocyclic residue substituted with 0-2 R⁴, and 5-10 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R⁴;

[0030] R¹″ is selected from H, C(O)R^(2b), C(O)NR²R^(2a), S(O)R^(2b), S(O)₂R^(2b), and SO₂NR²R^(2a);

[0031] R², at each occurrence, is selected from H, CF₃, C₁₋₆ alkyl, benzyl, C₃₋₆ carbocyclic residue substituted with 0-2 R^(4b), and 5-6 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R^(4b);

[0032] R^(2a), at each occurrence, is selected from H, CF₃, C₁₋₆ alkyl, benzyl, C₃₋₆ carbocyclic residue substituted with 0-2 R^(4b), and 5-6 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R^(4b);

[0033] R^(2b), at each occurrence, is selected from CF₃, C₁₋₄ alkoxy, C₁₋₆ alkyl, benzyl, C₃₋₆ carbocyclic residue substituted with 0-2 R^(4b), and 5-6 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R^(4b);

[0034] R^(2c), at each occurrence, is selected from CF₃, OH, C₁₋₄ alkoxy, C₁₋₆ alkyl, benzyl, C₃₋₆ carbocyclic residue substituted with 0-2 R^(4b), and 5-6 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R^(4b);

[0035] alternatively, R² and R^(2a) combine to form a 5 or 6 membered saturated, partially saturated or unsaturated ring substituted with 0-2 R^(4b) which contains from 0-1 additional heteroatoms selected from the group consisting of N, O, and S;

[0036] R³, at each occurrence, is selected from H, C₁₋₄ alkyl, and phenyl;

[0037] R^(3a), at each occurrence, is selected from H, C₁₋₄ alkyl, and phenyl;

[0038] A is selected from:

[0039] C₃₋₁₀ carbocyclic residue substituted with 0-2 R⁴, and

[0040] 5-10 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R⁴;

[0041] B is selected from:

[0042] X—Y, NR²R^(2a), C(═NR²)NR²R^(2a), NR²C(═NR²)NR²R^(2a),

[0043] C₃₋₁₀ carbocyclic residue substituted with 0-2 R^(4a), and

[0044] 5-10 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R^(4a);

[0045] X is selected from C₁₋₄ alkylene, —CR²(CR²R^(2b))(CH₂)_(t)—, —C(O)—, —C(═NR)—, —CR²(NR¹″R²)—, —CR²(OR²)—, —CR²(SR²)—, —C(O)CR²R^(2a)—, —CR²R^(2a)C(O), —S(O)_(p)—, —S(O)_(p)CR²R^(2a)—, —CR²R^(2a)S(O)_(p)—, —S(O)₂NR²—, —NR²S(O)₂—, —NR²S(O)₂CR²R^(2a)—, —CR²R^(2a)S(O)₂NR²—, —NR²S(O)₂NR²—, —C(O)NR²—, —NR²C(O)—, —C(O)NR²CR²R^(2a)—, —NR²C(O)CR²R^(2a)—, —CR²R^(2a)C(O)NR²—, —CR²R^(2a)NR²C(O)—, —NR²C(O)O—, —OC(O)NR²—, —NR²C(O)NR²—, —NR², —NR²CR²R^(2a)—, CR²R^(2a)NR²—, O, —CR²R^(2a)O—, and —OCR²R^(2a)—;

[0046] Y is selected from:

[0047] (CH₂)_(r)NR²R^(2a), provided that X—Y do not form a N—N, O—N, or S—N bond,

[0048] C₃₋₁₀ carbocyclic residue substituted with 0-2 R^(4a), and

[0049] 5-10 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R^(4a);

[0050] R⁴, at each occurrence, is selected from ═O, (CH₂)_(r)OR², halo, C₁₋₄ alkyl, —CN, NO₂, (CH₂)_(r)NR²R^(2a), (CH₂)_(r)C(O)R^(2b), NR²C(O)R^(2b), C(O)NR²R^(2a), NR²C(O)NR²R^(2a), CH(═NR²)NR²R^(2a), NHC(═NR²)NR²R^(2a), SO₂NR²R^(2a), NR²SO₂NR²R^(2a), NR²SO₂—C₁₋₄ alkyl, NR²SO₂R⁵, S(O)_(p)R⁵, (CF₂)_(r)CF₃, NCH₂R¹″, OCH₂R¹″, SCH₂R¹″, N(CH₂)₂(CH₂)_(t)R¹′, O(CH₂)₂(CH₂)_(t)R¹′, and S(CH₂)₂(CH₂)_(t)R¹′,

[0051] alternatively, one R⁴ is a 5-6 membered aromatic heterocycle containing from 1-4 heteroatoms selected from the group consisting of N, O, and S;

[0052] R^(4a), at each occurrence, is selected from ═O, (CH₂)_(r)OR², halo, C₁₋₄ alkyl, —CN, NO₂, (CH₂)_(r)NR²R^(2a), (CH₂)_(r)C(O)R^(2b), NR²C(O)R^(2b), C(O)NR²R^(2a), NR²C(O)NR²R^(2a), CH(═NR²)NR²R^(2a), NHC(═NR²)NR²R^(2a), SO₂NR²R^(2a), NR²SO₂NR²R^(2a), NR²SO₂—C₁₋₄ alkyl, NR²SO₂R⁵, S(O)_(p)R⁵, and (CF₂)_(r)CF₃;

[0053] alternatively, one R^(4a) is a 5-6 membered aromatic heterocycle containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-1 R⁵;

[0054] R^(4b), at each occurrence, is selected from ═O, (CH₂)_(r)OR³, halo, C₁₋₄ alkyl, —CN, NO₂, (CH₂)_(r)NR³R^(3a), (CH₂)_(r)C(O)R³, NR³C(O)R^(3a), C(O)NR³R^(3a), NR³C(O)NR³R^(3a), CH(═NR³)NR³R^(3a), NH³C (═NR³) NR³R^(3a), SO₂NR³R^(3a), NR³SO₂NR³R^(3a), NR³SO₂—C₁₋₄ alkyl, NR³SO₂CF₃, NR³SO₂-phenyl, S(O)_(p)CF₃, S(O)_(p)—C₁₋₄ alkyl, S(O)_(p)-phenyl, and (CF₂)_(r)CF₃;

[0055] R⁵, at each occurrence, is selected from CF₃, C₁₋₆ alkyl, phenyl substituted with 0-2 R⁶, and benzyl substituted with 0-2 R⁶;

[0056] R⁶, at each occurrence, is selected from H, OH, (CH₂)_(r)OR², halo, C₁₋₄ alkyl, CN, NO₂, (CH₂)_(r)NR²R^(2a),(CH₂)_(r)C(O)R^(2b), NR²C(O)R^(2b), NR²C(O)NR²R^(2a), CH(═NH)NH₂, NHC(═NH)NH₂, SO₂NR²R^(2a), NR²SO₂NR²R^(2a), and NR²SO₂C₁₋₁₄ alkyl;

[0057] R⁷, at each occurrence, is selected from H, OH, C₁₋₆ alkyl, C₁₋₆ alkylcarbonyl, C₁₋₆ alkoxy, C₁₋₄ alkoxycarbonyl, (CH₂)_(n)-phenyl, C₆₋₁₀ aryloxy, C₆₋₁₀ aryloxycarbonyl, C₆₋₁₀ arylmethylcarbonyl, C₁₋₄ alkylcarbonyloxy C₁₋₄ alkoxycarbonyl, C₆₋₁₀ arylcarbonyloxy C₁₋₄ alkoxycarbonyl, C₁₋₆ alkylaminocarbonyl, phenylaminocarbonyl, and phenyl C₁₋₄ alkoxycarbonyl;

[0058] R⁸, at each occurrence, is selected from H, C₁₋₆ alkyl and (CH₂) n-phenyl;

[0059] alternatively, R⁷ and R⁸ combine to form a 5 or 6 membered saturated, ring which contains from 0-1 additional heteroatoms selected from the group consisting of N, O, and S;

[0060] R⁹, at each occurrence, is selected from H, C₁₋₆ alkyl and (CH₂)_(n)-phenyl;

[0061] n, at each occurrence, is selected from 0, 1, 2, and 3;

[0062] m, at each occurrence, is selected from 0, 1, and 2;

[0063] p, at each occurrence, is selected from 0, 1, and 2;

[0064] q, at each occurrence is selected from 1 and 2;

[0065] r, at each occurrence, is selected from 0, 1, 2, and 3;

[0066] s, at each occurrence, is selected from 0, 1, and 2; and,

[0067] t, at each occurrence, is selected from 0 and 1.

[0068] [2] In a preferred embodiment, the present invention provides novel compounds of formulae Ia-Ib:

[0069] wherein;

[0070] Z is selected from a CH₂O, OCH₂, CH₂NH, NHCH₂, C(O), CH₂C(O), C(O)CH₂, NHC(O), C(O)NH, CH₂S(O)₂, S(O)₂(CH₂), SO₂NH, and NHSO₂, provided that Z does not form a N—N, N—O, NCH₂N, or NCH₂O bond with group A;

[0071] A is selected from one of the following carbocyclic and heterocyclic systems which are substituted with 0-2 R⁴;

[0072] phenyl, piperidinyl, piperazinyl, pyridyl, pyrimidyl, furanyl, morpholinyl, thiophenyl, pyrrolyl, pyrrolidinyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, triazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, benzofuranyl, benzothiofuranyl, indolyl, benzimidazolyl, benzoxazolyl, benzthiazolyl, indazolyl, benzisoxazolyl, benzisothiazolyl, and isoindazolyl;

[0073] B is selected from: Y, X—Y, NR²R^(2a), C(═NR²)NR²R^(2a), and NR²C(═NR²) NR²R^(2a);

[0074] X is selected from C₁₋₄ alkylene, —C(O)—, —C(═NR)—, —CR²(NR²R^(2a))—, —C(O)CR²R^(2a)—, —CR²R^(2a)C(O), —C(O)NR²—, —NR²C(O) —, —C(O)NR²CR²R^(2a)—, —NR²C(O)CR²R^(2a)—, —CR²R^(2a)C(O)NR²—, —CR²R^(2a)NR²C(O)—, —NR²C(O)NR²—, —NR²—, —NR²CR²R^(2a)—, —CR²R^(2a)NR²—, O, —CR²R^(2a)O—, and —OCR²R^(2a)—;

[0075] Y is NR²R^(2a), provided that X—Y do not form a N—N or O—N bond;

[0076] alternatively, Y is selected from one of the following carbocyclic and heterocyclic systems which are substituted with 0-2 R^(4a);

[0077] cylcopropyl, cyclopentyl, cyclohexyl, phenyl, piperidinyl, piperazinyl, pyridyl, pyrimidyl, furanyl, morpholinyl, thiophenyl, pyrrolyl, pyrrolidinyl, oxazolyl, isoxazolyl, isoxazolinyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, triazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, benzofuranyl, benzothiofuranyl, indolyl, benzimidazolyl, benzoxazolyl, benzthiazolyl, indazolyl, benzisoxazolyl, benzisothiazolyl, and isoindazolyl;

[0078] alternatively, Y is selected from the following bicyclic heteroaryl ring systems:

[0079] K is selected from O, S, NH, and N.

[0080] [3] In a more preferred embodiment, the present invention provides novel compounds of formulae Ia-Ib, wherein;

[0081] Z is selected from a C(O), CH₂C(O), C(O)CH₂, NHC(O), C(O)NH, C(O)N(CH₃), CH₂S(O)₂, S(O)₂(CH₂), SO₂NH, and NHSO₂, provided that Z does not form a N—N or NCH₂N bond with group A.

[0082] [4] In an even more preferred embodiment, the present invention provides novel compounds of formulae Ia-Ib, wherein;

[0083] E is phenyl substituted with R or 2-pryidyl substituted with R;

[0084] D is selected from C(O)NH₂, C(═NH)NH₂, CH₂NH₂, CH₂NHCH₃, CH(CH₃)NH₂, and C(CH₃)₂NH₂; and,

[0085] R is selected from H, OCH₃, Cl, and F.

[0086] [5] In further preferred embodiment, the present invention provides novel compounds of formulae Ia-Ib, wherein;

[0087] D—E is selected from 3-amidinophenyl, 3-aminomethylphenyl, 3-aminocarbonylphenyl, 3-(methylaminomethyl)phenyl, 3-(1-aminoethyl)phenyl, 3-(2-amino-2-propyl)phenyl, 4-chloro-3-amidinophenyl, 4-chloro-3-aminomethylphenyl, 4-chloro-3-(methylaminomethyl)phenyl, 4-fluoro-3-amidinophenyl, 4-fluoro-3-aminomethylphenyl, 4-fluoro-3-(methylaminomethyl)phenyl, 6-amidinopyrid-2-yl, 6-aminomethylpyrid-2-yl, 6-aminocarbonylpyrid-2-yl, 6-(methylaminomethyl)pyrid-2-yl, 6-(1-aminoethyl)pyrid-2-yl, and 6-(2-amino-2-propyl)pyrid-2-yl.

[0088] [6] In another even more preferred embodiment, the present invention provides novel compounds of formulae Ia-Ib, wherein;

[0089] Z is C(O)CH₂ and CONH, provided that Z does not form a N—N bond with group A;

[0090] A is selected from phenyl, pyridyl, and pyrimidyl, and is substituted with 0-2 R⁴; and,

[0091] B is selected from X—Y, phenyl, pyrrolidino, morpholino, 1,2,3-triazolyl, and imidazolyl, and is substituted with 0-1 R^(4a);

[0092] R⁴, at each occurrence, is selected from OH, (CH₂)_(r)OR², halo, C₁₋₄ alkyl, (CH₂)_(r)NR²R^(2a), and (CF₂)_(r)CF₃;

[0093] R^(4a) is selected from C₁₋₄ alkyl, CF₃, S(O)_(p)R⁵, SO₂NR²R^(2a), and 1-CF₃-tetrazol-2-yl;

[0094] R⁵, at each occurrence, is selected from CF₃, C₁₋₆ alkyl, phenyl, and benzyl;

[0095] X is CH₂ or C(O); and,

[0096] Y is selected from pyrrolidino and morpholino.

[0097] [7] In another further preferred embodiment, the present invention provides novel compounds of formulae Ia-Ib, wherein;

[0098] A is selected from the group: phenyl, 2-pyridyl, 3-pyridyl, 2-pyrimidyl, 2-Cl-phenyl, 3-Cl-phenyl, 2-F-phenyl, 3-F-phenyl, 2-methylphenyl, 2-aminophenyl, and 2-methoxyphenyl; and,

[0099] B is selected from the group: 2-CF₃-phenyl, 2-(aminosulfonyl)phenyl, 2-(methylaminosulfonyl)phenyl, 2-(dimethylaminosulfonyl)phenyl, 1-pyrrolidinocarbonyl, 2-(methylsulfonyl)phenyl, 4-morpholino, 2-(1′-CF₃-tetrazol-2-yl)phenyl, 4-morpholinocarbonyl, 2-methyl-1-imidazolyl, 5-methyl-1-imidazolyl, 2-methylsulfonyl-1-imidazolyl and, 5-methyl-1,2,3-triazolyl.

[0100] [8] In another even more preferred embodiment, the present invention provides novel compounds of formulae Ia-Ib, wherein;

[0101] E is phenyl substituted with R or 2-pyridyl substituted with R;

[0102] D is selected from C(O)NH₂, C(═NH)NH₂, CH₂NH₂, CH₂NHCH₃, CH(CH₃)NH₂, and C(CH₃)₂NH₂; and,

[0103] R is selected from H, OCH₃, Cl, and F;

[0104] Z is C(6)CH₂ and CONH, provided that Z does not form a N—N bond with group A;

[0105] A is selected from phenyl, pyridyl, and pyrimidyl, and is substituted with 0-2 R⁴; and,

[0106] B is selected from X—Y, phenyl, pyrrolidino, morpholino, 1,2,3-triazolyl, and imidazolyl, and is substituted with 0-1 R^(4a);

[0107] R⁴, at each occurrence, is selected from OH, (CH₂)_(r)OR², halo, C₁₋₄ alkyl, (CH₂)_(r)NR²R^(2a), and (CF₂)_(r)CF₃;

[0108] R^(4a) is selected from C₁₋₄ alkyl, CF₃, S(O)_(p)R⁵, SO₂NR²R^(2a), and 1-CF₃-tetrazol-2-yl;

[0109] R⁵, at each occurrence, is selected from CF₃, C₁₋₆ alkyl, phenyl, and benzyl;

[0110] X is CH₂ or C(O); and,

[0111] Y is selected from pyrrolidino and morpholino.

[0112] [9] In another further preferred embodiment, the present invention provides novel compounds of formulae Ia-Ib, wherein;

[0113] D—E is selected from 3-amidinophenyl, 3-aminomethylphenyl, 3-aminocarbonylphenyl, 3-(methylaminomethyl)phenyl, 3-(1-aminoethyl)phenyl, 3-(2-amino-2-propyl)phenyl, 4-chloro-3-amidinophenyl, 4-chloro-3-aminomethylphenyl, 4-chloro-3-(methylaminomethyl)phenyl, 4-fluoro-3-amidinophenyl, 4-fluoro-3-aminomethylphenyl, 4-fluoro-3-(methylaminomethyl)phenyl, 6-amidinopyrid-2-yl, 6-aminomethylpyrid-2-yl, 6-aminocarbonylpyrid-2-yl, 6-(methylaminomethyl)pyrid-2-yl, 6-(1-aminoethyl)pyrid-2-yl, 6-(2-amino-2-propyl)pyrid-2-yl;

[0114] A is selected from the group: phenyl, 2-pyridyl, 3-pyridyl, 2-pyrimidyl, 2-Cl-phenyl, 3-Cl-phenyl, 2-F-phenyl, 3-F-phenyl, 2-methylphenyl, 2-aminophenyl, and 2-methoxyphenyl; and,

[0115] B is selected from the group: 2-CF₃-phenyl, 2-(aminosulfonyl)phenyl, 2-(methylaminosulfonyl)phenyl, 2-(dimethylaminosulfonyl)phenyl, 1-pyrrolidinocarbonyl, 2-(methylsulfonyl)phenyl, 4-morpholino, 2-(1′-CF₃-tetrazol-2-yl)phenyl, 4-morpholinocarbonyl, 2-methyl-1-imidazolyl, 5-methyl-1-imidazolyl, 2-methylsulfonyl-1-imidazolyl and, 5-methyl-1,2,3-triazolyl.

[0116] [10] In a still further preferred embodiment, the present invention provides a novel compound of formula Ia.

[0117] [11] In another still further preferred embodiment, the present invention provides a novel compound of formula Ib.

[0118] [12] In another even more preferred embodiment, the present invention provides novel compounds of formulae Ia-Ib, wherein;

[0119] D is selected from C(═NR⁸)NR⁷R⁹, C(O)NR⁷R⁸, NR⁷R⁸, and CH₂NR⁷R⁸;

[0120] E is phenyl substituted with R or pyridyl substituted with R;

[0121] R is selected from H, Cl, F, OR³, CH₃, CH₂CH₃, OCF₃, and CF₃;

[0122] Z is selected from C(O), CH₂C(O), C(O)CH₂, NHC(O), and C(O)NH, provided that Z does not form a N—N bond with group A;

[0123] R^(1a) and R^(1b) are, at each occurrence, independently selected from H, —(CH₂)_(r)—R¹′, NCH₂R¹, OCH₂R¹, SCH₂R¹, N(CH₂)₂(CH₂)_(t)R¹′, O(CH₂)₂(CH₂)_(t)R¹′, and S(CH₂) 2 (CH₂)_(t)R¹′;

[0124] R^(1c) is selected from H, —(CH₂) q-R₁, C₁₋₃ alkyl, C(O)R^(2c), (CF₂)_(r)CO₂R^(2c), and C(O)NR²R^(2a); R¹′, at each occurrence, is selected from H, C₁₋₃ alkyl, halo, (CF₂)_(r)CF₃, OR², NR²R^(2a), C(O)R^(2c), (CF₂)_(r)CO₂R^(2c), S(O)_(p)R^(2b), NR²(CH₂)_(r)OR², NR²C(O)R^(2b), NR²C(O)₂R^(2b), C(O)NR²R^(2a), SO₂NR²R^(2a), and NR²SO₂R^(2b);

[0125] A is selected from one of the following carbocyclic and heterocyclic systems which are substituted with 0-2 R⁴;

[0126] phenyl, piperidinyl, piperazinyl, pyridyl, pyrimidyl, furanyl, morpholinyl, thiophenyl, pyrrolyl, pyrrolidinyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, and imidazolyl;

[0127] B is selected from: Y, X—Y, NR²R^(2a), C(═NR²)NR²R^(2a), and NR²C (═NR²) NR²R^(2a);

[0128] X is selected from CH₂, —CR²(CR²R^(2b))(CH₂)_(t)—, —C(O)—, —C(═NR)—, —CH(NR²R^(2a))—, —C(O)NR²—, —NR²C(O)—, —NR²C(O)NR²—, —NR²—, and O;

[0129] Y is NR²R^(2a), provided that X—Y do not form a N—N or O—N bond;

[0130] alternatively, Y is selected from one of the following carbocyclic and heterocyclic systems which are substituted with 0-2 R^(4a);

[0131] phenyl, piperidinyl, piperazinyl, pyridyl, pyrimidyl, furanyl, morpholinyl, thiophenyl, pyrrolyl, pyrrolidinyl, oxazolyl, isoxazolyl, isoxazolinyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, triazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, and 1,3,4-triazolyl;

[0132] R⁴, at each occurrence, is selected from ═O, OH, Cl, F, C₁₋₄ alkyl, (CH₂)_(r) NR²R^(2a), (CH₂)_(r)C(O)R^(2b), NR²C(O)R^(2b), C(O)NR²R^(2a), CH(═NH)NH₂, NHC(═NH)NH₂, SO₂NR²R^(2a), NR²SO₂—C₁₋₄ alkyl, NR²SO₂R⁵, S(O)_(p)R⁵, and (CF₂)_(r)CF₃;

[0133] R^(4a), at each occurrence, is selected from ═O, OH, Cl, F, C₁₋₄ alkyl, (CH₂)_(r) NR²R^(2a), (CH₂)_(r)C(O)R^(2b), NR²C(O)R^(2b), C(O)NR²R^(2a), CH(═NH)NH₂, NHC(═NH)NH₂, SO₂NR²R^(2a), NR²SO₂—C₁₋₄ alkyl, NR²SO₂R⁵, S(O)_(p)R⁵, (CF₂)_(r)CF₃, and 1-CF₃-tetrazol-2-yl;

[0134] R⁵, at each occurrence, is selected from CF₃, C₁₋₆ alkyl, phenyl substituted with 0-2 R⁶, and benzyl substituted with 0-2 R⁶;

[0135] R⁶, at each occurrence, is selected from H, ═O, OH, OR², Cl, F, CH₃, CN, NO₂, (CH₂)_(r)NR²R^(2a), (CH₂)_(r)C(O)R^(2b), NR²C(O)R^(2b), CH(═NH)NH₂, NHC(═NH)NH₂, and SO₂NR²R^(2a);

[0136] R⁷, at each occurrence, is selected from H, OH, C₁₋₆ alkyl, C₁₋₆ alkylcarbonyl, C₁₋₆ alkoxy, C₁₋₄ alkoxycarbonyl, benzyl, C₆₋₁₀ aryloxy, C₆₋₁₀ aryloxycarbonyl, C₆₋₁₀ arylmethylcarbonyl, C₁₋₄ alkylcarbonyloxy C₁₋₄ alkoxycarbonyl, C₆₋₁₀ arylcarbonyloxy C₁₋₄ alkoxycarbonyl, C₁₋₆ alkylaminocarbonyl, phenylaminocarbonyl, and phenyl C₁₋₄ alkoxycarbonyl;

[0137] R⁸, at each occurrence, is selected from H, C₁₋₆ alkyl and benzyl; and alternatively, R⁷ and R⁸ combine to form a morpholino group; and,

[0138] R⁹, at each occurrence, is selected from H, C₁₋₆ alkyl and benzyl.

[0139] [13] In a another further preferred embodiment, the present invention provides novel compounds of formulae Ia-Ib, wherein;

[0140] E is phenyl substituted with R or 2-pyridyl substituted with R;

[0141] R is selected from H, Cl, F, OCH₃, CH₃, OCF₃, and CF₃;

[0142] Z is selected from a C(O)CH₂ and C(O)NH, provided that Z does not form a N—N bond with group A;

[0143] R^(1a), at each occurrence, is selected from H, CH₃, CH₂CH₃, Cl, F, CF₃, OCH₃, NR²R^(2a), S(O)_(p)R^(2b), CH₂S(O)_(p)R^(2b), CH₂NR²S(O)_(p)R^(2b), C(O)R^(2c), CH₂C(O)R^(2c), C(O)NR²R^(2a), and SO₂NR²R^(2a);

[0144] R^(1b) is selected from H, CH₃, CH₂CH₃, Cl, F, CF₃, OCH₃, NR²R^(2a), S(O)_(p)R^(2b), CH₂S(O)_(p)R^(2b), CH₂NR²S(O)_(p)R^(2b), C(O)R^(2c), CH₂C(O)R^(2c), C(O)NR²R^(2a), and SO₂NR²R^(2a);

[0145] R^(1c) is selected from H, CH₃, CH₂CH₃, CF₃, CH₂S(O)_(p)R^(2b), CH₂NR²S(O)_(p)R^(2b), C(O)R^(2c), CH₂C(O)R^(2c), and C(O)NR²R^(2a);

[0146] A is selected from one of the following carbocyclic and heterocyclic systems which are substituted with 0-2 R⁴;

[0147] phenyl, pyridyl, pyrimidyl, furanyl, thiophenyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, and imidazolyl;

[0148] B is selected from: Y and X—Y;

[0149] X is selected from CH₂, —CR²(CR²R^(2b))—, —C(O)—, —C(═NR)—, —CH(NR²R^(2a))—, —C(O)NR²—, —NR²C(O)—, —NR²C(O)NR²—, —NR²—, and O;

[0150] Y is NR²R^(2a), provided that X—Y do not form a N—N or O—N bond; alternatively, Y is selected from one of the following carbocyclic and heterocyclic systems which are substituted with 0-2 R^(4a);

[0151] phenyl, piperidinyl, piperazinyl, pyridyl, pyrimidyl, furanyl, morpholinyl, thiophenyl, pyrrolyl, pyrrolidinyl, oxazolyl, isoxazolyl, isoxazolinyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, triazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, and 1,3,4-triazolyl;

[0152] R², at each occurrence, is selected from H, CF₃, CH₃, benzyl, and phenyl;

[0153] R^(2a), at each occurrence, is selected from H, CF₃, CH₃, benzyl, and phenyl;

[0154] R^(2b), at each occurrence, is selected from CF₃, OCH₃, CH₃, benzyl, and phenyl;

[0155] R^(2c), at each occurrence, is selected from CF₃, OH, OCH₃, CH₃, benzyl, and phenyl;

[0156] alternatively, R² and R^(2a) combine to form a 5 or 6 membered saturated, partially unsaturated, or unsaturated ring which contains from 0-1 additional heteroatoms selected from the group consisting of N, O, and S;

[0157] R³, at each occurrence, is selected from H, CH₃, CH₂CH₃, and phenyl;

[0158] R^(3a), at each occurrence, is selected from H, CH₃, CH₂CH₃, and phenyl;

[0159] R⁴, at each occurrence, is selected from OH, Cl, F, CH₃, CH₂CH₃, NR²R^(2a), CH₂NR²R^(2a), C(O)R^(2b), NR²C(O)R^(2b), C(O)NR²R^(2a), and CF₃;

[0160] R^(4a), at each occurrence, is selected from OH, Cl, F, CH₃, CH₂CH₃, NR²R^(2a), CH₂NR²R^(2a), C(O)R^(2b), C(O)NR²R^(2a), SO₂NR²R^(2a), S(O)_(p)R⁵, CF₃, and 1-CF₃-tetrazol-2-yl;

[0161] R⁵, at each occurrence, is selected from CF₃, C₁₋₆ alkyl, phenyl substituted with 0-2 R⁶, and benzyl substituted with 1 R⁶;

[0162] R⁶, at each occurrence, is selected from H, OH, OCH₃, Cl, F, CH₃, CN, NO₂, NR²R^(2a), CH₂NR²R^(2a), and SO₂NR²R^(2a);

[0163] R⁷, at each occurrence, is selected from H, OH, C₁₋₃ alkyl, C₁₋₃ alkylcarbonyl, C₁₋₃ alkoxy, C₁₋₄ alkoxycarbonyl, benzyl, phenoxy, phenoxycarbonyl, benzylcarbonyl, C₁₋₄ alkylcarbonyloxy C₁₋₄ alkoxycarbonyl, phenylcarbonyloxy C₁₋₄ alkoxycarbonyl, C₁₋₆ alkylaminocarbonyl, phenylaminocarbonyl, and phenyl C₁₋₄ alkoxycarbonyl;

[0164] R⁸, at each occurrence, is selected from H, CH₃, and benzyl; and,

[0165] alternatively, R⁷ and R⁸ combine to form a morpholino group;

[0166] R⁹, at each occurrence, is selected from H, CH₃, and benzyl.

[0167] [14] In a another still further preferred embodiment, the present invention provides novel compounds of formulae Ia-Ib, wherein;

[0168] R^(1a), at each occurrence, is selected from H, CH₃, CH₂CH₃, Cl, F, CF₃, OCH₃, NR²R^(2a), S(O)_(p)R^(2b), C(O)NR²R^(2a), CH₂S(O)_(p)R^(2b), CH₂NR²S(O)_(p)R^(2b), C(O)R^(2c), CH₂C(O)R^(2c), and SO₂NR²R^(2a);

[0169] R^(1b) is selected from H, CH₃, CH₂CH₃, Cl, F, CF₃, OCH₃, NR²R^(2a), S(O)_(p)R^(2b), C(O)NR²R^(2a), CH₂S(O)_(p)R^(2b), CH₂NR²S(O)_(p)R^(2b), C(O)R^(2b), CH₂C(O)R^(2b), and SO₂NR²R^(2a);

[0170] R^(1c) is selected from H, CH₃, CH₂CH₃, CF₃, C(O)NR²R^(2a), CH₂S(O)_(p)R^(2b), CH₂NR²S(O)_(p)R^(2b), C(O)R^(2b), and CH₂C(O)R^(2b);

[0171] A is selected from one of the following carbocyclic and heterocyclic systems which are substituted with 0-2 R⁴;

[0172] phenyl, pyridyl, and pyrimidyl;

[0173] B is selected from: Y and X—Y;

[0174] X is selected from —C(O)— and O;

[0175] Y is NR²R^(2a), provided that X—Y do not form a O—N bond;

[0176] alternatively, Y is selected from one of the following carbocyclic and heterocyclic systems which are substituted with 0-2 R^(4a);

[0177] phenyl, piperazinyl, pyridyl, pyrimidyl, morpholinyl, pyrrolidinyl, imidazolyl, and 1,2,3-triazolyl;

[0178] R², at each occurrence, is selected from H, CF₃, CH₃, benzyl, and phenyl;

[0179] R^(2a), at each occurrence, is selected from H, CF₃, CH₃, benzyl, and phenyl;

[0180] R^(2b), at each occurrence, is selected from CF₃, OCH₃, CH₃, benzyl, and phenyl;

[0181] R^(2c), at each occurrence, is selected from CF₃, OH, OCH₃, CH₃, benzyl, and phenyl;

[0182] alternatively, R² and R^(2a) combine to form a ring system selected from pyrrolidinyl, piperazinyl and morpholino;

[0183] R⁴, at each occurrence, is selected from Cl, F, CH₃, NR²R^(2a), and CF₃;

[0184] R^(4a), at each occurrence, is selected from Cl, F, CH₃, SO₂NR²R^(2a), S(O)_(p)R⁵, and CF₃; and,

[0185] R⁵, at each occurrence, is selected from CF₃ and CH₃.

[0186] [15] Specifically preferred compounds of the present invention are selected from the group:

[0187] 1-(3-amidinophenyl)-5-[[(2′-methylsulfonyl-[1,1′]-biphen-4-yl)-aminocarbonyl]-3-trifluoromethyl-pyrazoline; and,

[0188] 1-(3-aminomethylphenyl)-5-[[(2′-methylsulfonyl-[1,1′]-biphen-4-yl)-aminocarbonyl]-3-trifluoromethyl-pyrazoline;

[0189] and pharmaceutically acceptable salts thereof.

[0190] In a second embodiment, the present invention provides novel pharmaceutical compositions, comprising: a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt form thereof.

[0191] In a third embodiment, the present invention provides a novel method for treating or preventing a thromboembolic disorder, comprising: administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt form thereof.

DEFINITIONS

[0192] The compounds herein described may have asymmetric centers. Compounds of the present invention containing an asymmetrically substituted atom may be isolated in optically active or racemic forms. It is well known in the art how to prepare optically active forms, such as by resolution of racemic forms or by synthesis from optically active starting materials. Many geometric isomers of olefins, C═N double bonds, and the like can also be present in the compounds described herein, and all such stable isomers are contemplated in the present invention. Cis and trans geometric isomers of the compounds of the present invention are described and may be isolated as a mixture of isomers or as separated isomeric forms. All chiral, diastereomeric, racemic forms and all geometric isomeric forms of a structure are intended, unless the specific stereochemistry or isomeric form is specifically indicated.

[0193] The term “substituted,” as used herein, means that any one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valency is not exceeded, and that the substitution results in a stable compound. When a substitent is keto (i.e., ═O), then 2 hydrogens on the atom are replaced.

[0194] When any variable (e.g., R⁶) occurs more than one time in any constituent or formula for a compound, its definition at each occurrence is independent of its definition at every other occurrence. Thus, for example, if a group is shown to be substituted with 0-2 R⁶, then said group may optionally be substituted with up to two R⁶ groups and R⁶ at each occurrence is selected independently from the definition of R⁶. Also, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.

[0195] When a bond to a substituent is shown to cross a bond connecting two atoms in a ring, then such substituent may be bonded to any atom on the ring. When a substituent is listed without indicating the atom via which such substituent is bonded to the rest of the compound of a given formula, then such substituent may be bonded via any atom in such substituent. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.

[0196] As used herein, “C₁₋₆ alkyl” is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms, examples of which include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, t-butyl, pentyl, and hexyl; “Alkenyl” is intended to include hydrocarbon chains of either a straight or branched configuration and one or more unsaturated carbon-carbon bonds which may occur in any stable point along the chain, such as ethenyl, propenyl, and the like.

[0197] “Halo” or “halogen” as used herein refers to fluoro, chloro, bromo, and iodo; and “counterion” is used to represent a small, negatively charged species such as chloride, bromide, hydroxide, acetate, sulfate, and the like.

[0198] As used herein, “carbocycle” or “carbocyclic residue” is intended to mean any stable 3- to 7-membered monocyclic or bicyclic or 7- to 13-membered bicyclic or tricyclic, any of which may be saturated, partially unsaturated, or aromatic. Examples of such carbocycles include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, cyclooctyl, [3.3.0]bicyclooctane, [4.3.0]bicyclononane, [4.4.0]bicyclodecane (decalin), [2.2.2]bicyclooctane, fluorenyl, phenyl, naphthyl, indanyl, adamantyl, or tetrahydronaphthyl (tetralin).

[0199] As used herein, the term “heterocycle” or “heterocyclic system” is intended to mean a stable 5- to 7-membered monocyclic or bicyclic or 7- to 10-membered bicyclic heterocyclic ring which is saturated partially unsaturated or unsaturated (aromatic), and which consists of carbon atoms and from 1 to 4 heteroatoms independently selected from the group consisting of N, O and S and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring. The nitrogen and sulfur heteroatoms may optionally be oxidized. The heterocyclic ring may be attached to its pendant group at any heteroatom or carbon atom which results in a stable structure. The heterocyclic rings described herein may be substituted on carbon or on a nitrogen atom if the resulting compound is stable. If specifically noted, a nitrogen in the heterocycle may optionally be quaternized. It is preferred that when the total number of S and O atoms in the heterocycle exceeds 1, then these heteroatoms are not adjacent to one another. It is preferred that the total number of S and O atoms in the heterocycle is not more than 1. As used herein, the term “aromatic heterocyclic system” is intended to mean a stable 5- to 7-membered monocyclic or bicyclic or 7- to 10-membered bicyclic heterocyclic aromatic ring which consists of carbon atoms and from 1 to 4 heterotams independently selected from the group consisting of N, O and S. It is preferred that the total number of S and O atoms in the aromatic heterocycle is not more than 1.

[0200] Examples of heterocycles include, but are not limited to, 1H-indazole, 2-pyrrolidonyl, 2H,6H-1,5,2-dithiazinyl, 2H-pyrrolyl, 3H-indolyl, 4-piperidonyl, 4aH-carbazole, 4H-quinolizinyl, 6H-1,2,5-thiadiazinyl, acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazalonyl, carbazolyl, 4aH-carbazolyl, β-carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl., oxazolyl, oxazolidinylperimidinyl, phenanthridinyl, phenanthrolinyl, phenarsazinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, pteridinyl, piperidonyl, 4-piperidonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, carbolinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, xanthenyl. Preferred heterocycles include, but are not limited to, pyridinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, indolyl, benzimidazolyl, 1H-indazolyl, oxazolidinyl, benzotriazolyl, benzisoxazolyl, oxindolyl, benzoxazolinyl, or isatinoyl. Also included are fused ring and spiro compounds containing, for example, the above heterocycles.

[0201] The phrase “pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.

[0202] As used herein, “pharmaceutically acceptable salts” refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. The pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, and the like.

[0203] The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418, the disclosure of which is hereby incorporated by reference.

[0204] “Prodrugs” are intended to include any covalently bonded carriers which release the active parent drug according to formula (I) in vivo when such prodrug is administered to a mammalian subject. Prodrugs of a compound of formula (I) are prepared by modifying functional groups present in the compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compound. Prodrugs include compounds of formula (I) wherein a hydroxy, amino, or sulfhydryl group is bonded to any group that, when the prodrug or compound of formula (I) is administered to a mammalian subject, cleaves to form a free hydroxyl, free amino, or free sulfhydryl group, respectively. Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohol and amine functional groups in the compounds of formula (I), and the like. Preferred prodrugs are amidine prodrugs wherein D is C(═NR⁷)NH₂ or its tautomer C(═NH)NHR⁷ and R⁷ is selected from OH, C₁₋₄ alkoxy, C₆₋₁₀ aryloxy, C₁₋₄ alkoxycarbonyl, C₆₋₁₀ aryloxycarbonyl, C₆₋₁₀ arylmethylcarbonyl, C₁₋₄ alkylcarbonyloxy C₁₋₄ alkoxycarbonyl, and C₆₋₁₀ arylcarbonyloxy C₁₋₄ alkoxycarbonyl. More preferred prodrugs are where R⁷ is OH, methoxy, ethoxy, benzyloxycarbonyl, methoxycarbonyl, and methylcarbonyloxymethoxycarbonyl.

[0205] “Stable compound” and “stable structure” are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.

SYNTHESIS

[0206] The compounds of the present invention can be prepared in a number of ways known to one skilled in the art of organic synthesis. The compounds of the present invention can be synthesized using the methods described below, together with synthetic methods known in the art of synthetic organic chemistry, or by variations thereon as appreciated by those skilled in the art. Preferred methods include, but are not limited to, those described below. The reactions are performed in a solvent appropriate to the reagents and materials employed and suitable for the transformations being effected. It will be understood by those skilled in the art of organic synthesis that the functionality present on the molecule should be consistent with the transformations proposed. This will sometimes require a judgment to modify the order of the synthetic steps or to select one particular process scheme over another in order to obtain a desired compound of the invention. It will also be recognized that another major consideration in the planning of any synthetic route in this field is the judicious choice of the protecting group used for protection of the reactive functional groups present in the compounds described in this invention. An authoritative account describing the many alternatives to the trained practitioner is Greene and Wuts (Protective Groups In Organic Synthesis, Wiley and Sons, 1991). All references cited herein are hereby incorporated in their entirety herein by reference.

[0207] Pyrazolines of this invention can be easily prepared via [3+2] cycloaddition of bromo or chloro hydrazone with an appropriate acrylate according to the methodology described by Tewari R. S. and Parihar Tetrahedron 1983, 39, 129-136, or Krayushkin, M. M. et. al Izv. Akad. Nauk, Ser. Khim. 1994, 1, 114-117.

[0208] Pyrazoline 5-esters can also be prepared by the treatment of an appropriately substituted hydrazone with lead tetraacetate and an appropriate acrylate in a THF/benzene solvent system according to the procedure of Sasaki T, et. al. Bull. Chem Soc. Jpn. 1970, 43, 1254.

[0209] Another method of obtaining pyrazoline 5-esters is the condensation of an appropriate phenyl or heteroaryl hydrazine with an approptiate 2-oxoglutaconate according to Blitzke, T. et. al. J. Prakt. Chem. 1993, 335(8), 683.

[0210] Alternatively the pyrazoline ester can be prepared by treatment of a diazo-trifluoromethyl derivative with excess acrylate or acrolein in the presence of excess pyridine (Doyle, M. 0. et. al. J. Heterocyclic Chem. 1983, 20, 943).

[0211] Cycloadditions as described above but with di-substituted olefins should result in the formation of regio-adducts which can be easily separated by standard chromatographic techniques.

[0212] It is understood by those in the art of organic synthesis that such cycloadditions can also be carried out with a wide variety of electron withdrawing olefins with functionalities such as nitro, sulfonyl, sulfonamido, nitrile, phosphate etc. These in turn can be derivatized to appropriate compounds of the present invention.

[0213] The pyrazoline carboxyesters obtained via any of the above mentioned methodologies can be converted to the amide derivatives via the acid, acid chloride coupling methodlogies or a direct Weinreb (trimethylaluminum, aniline in dichloromethane) coupling technique known to those in the art of organic synthesis. A variety of anilines or amines can be coupled via these methodologies to afford the desired compounds.

[0214] Alternatively the ester can be hydrolysed and converted to an amino functionality via the Curtius rearrangement. This in turn can be derivatised to obtain an amido, sulfonamido or urea derivative.

[0215] Pyrazolines wherein s is other than 0 can be prepared by alkylation of an appropriate pyrazoline.

[0216] The electrophile can consist of simple alkyl halides to heteroaryl alkyl halides. Some of the heteroaryl alkyl groups can include pyridyl, pyrimidyl, imidazolyl etc.

[0217] In cases wherein D is a nitrile can be further converted to an amidine functionality via the standard Pinner-amidine reaction sequence known to those in the art or can be converted to the benzylamine via reduction in an acidic media or can be converted to the secondary and tertiary amine via the DIBAH/MeMgCl or MeMgBr/CeCl₃ methodologies outlined below.

[0218] Compounds wherein D is a nitro can be reduced under catalytic Pd/C/MeOH techniques or SnCl₂/EtOAc or Zn/AcOH conditions to afford the desired amino derivatives.

[0219] Enantiomers of the pyrazolines can be easily obtained either via lipase hydrolysis of its esters or resolution with common chiral bases known to those in the art.

[0220] 1,2,3-Triazolines can be synthesized via the cycloaddition methodology however in this case the dipole is an aryl azide and the dipolarophile is a variety of olefins bearing an electron withdrawing group such as an ester, amide or sulfonamide.

[0221] 1,2,4-Triazolines can be prepared via the methods of Sandhy J. S. et. al. Heterocycles 1985, 23(5), 1143, and Heterocycles 1985, 23(5), 1123, by the method described in the scheme below.

[0222] The triazoline esters can then subjected to the standard coupling procedures discussed above to afford the desired amide analogs. These can then further modified to the prepare compounds of the present invention.

[0223] Compounds of the present invention wherein AB is a biphenylamine or similar amine may be prepared as shown in the following scheme. 4-Bromoaniline can be protected as Boc-derivative and coupled to a phenylboronic acid under Suzuki conditions (Bioorg. Med. Chem. Lett. 1994, 189). Deprotection with TFA provides the aminobiphenyl compound. Other similar amines wherein A and/or B are heterocycles can be prepared by the same method using appropiately substituted boronic acids and arylbromide. The bromoaniline can also be linked to the core ring structures first as described above, and then undergo a Suzuki reaction to give the desired product.

[0224] Compounds of the present invention wherein A—B is A—X—Y can be prepared like the piperazine derivative shown below.

[0225] The following scheme shows how one can couple cyclic groups wherein X═NH, O, or S.

[0226] When B is defined as X—Y, the following description applies. Groups A and B are available either through commercial sources, known in the literature or readily synthesized by the adaptation of standard procedures known to practioners skilled in the art of organic synthesis. The required reactive functional groups appended to analogs of A and B are also available either through commercial sources, known in the literature or readily synthesized by the adaptation of standard procedures known to practioners skilled in the art of organic synthesis. In the tables that follow the chemistry required to effect the coupling of A to B is outlined. TABLE A Preparation of Amide, Ester, Urea, Sulfonamide and Sulfamide linkages between A and B. then the reactive to give the Rxn. substituent of following product No. if A contains: Y is: A-X-Y: A-NHR² as a ClC(O)-Y A-NR²-C(O)-Y substituent 2 a secondary NH ClC(O)-Y A-C(O)-Y as part of a ring or chain 3 A-OH as a ClC(O)-Y A-O-C(O)-Y substituent 4 A-NHR² as a ClC(O)-CR²R^(2a)-Y A-NR²-C(O)-CR²R^(2a)-Y substituent 5 a secondary NH ClC(O)-CR²R^(2a)-Y A-C(O)-CR²R^(2a)-Y as part of a ring or chain 6 A-OH as a ClC(O)-CR²R^(2a)-Y A-O-C(O)-CR²R^(2a)-Y substituent 7 A-NHR³ as a ClC(O)NR²-Y A-NR²-C(O)NR²-Y substituent 8 a secondary NH ClC(O)NR²-Y A-C(O)NR²-Y as part of a ring or chain 9 A-OH as a ClC(O)NR²-Y A-O-C(O)NR²-Y substituent 10 A-NHR^(2 as a) ClSO₂-Y A-NR²-SO₂-Y substituent 11 a secondary NH ClSO₂-Y A-SO₂-Y as part of a ring or chain 12 A-NHR^(2 as a) ClSO₂-CR²R^(2a)-Y A-NR²-SO₂-CR²R^(2a)-Y substituent 13 a secondary NH ClSO₂-CR²R^(2a)-Y A-SO₂-CR²R^(2a)-Y as part of a ring or chain 14 A-NHR² as a ClSO₂-NR²-Y A-NR²-SO₂-NR²-Y substituent 15 a secondary NH ClSO₂-NR²-Y A-SO₂-NR²-Y as part of a ring or chain 16 A-C(O)Cl HO-Y as a A-C(O)-O-Y substituent 17 A-C(O)Cl NHR²-Y as a A-C(O)-NR²-Y substituent 18 A-C(O)Cl a secondary NH A-C(O)-Y as part of a ring or chain 19 A-CR²R^(2a)C(O)Cl HO-Y as a A-CR²R^(2a)C(O)-O-Y substituent 20 A-CR²R^(2a)C(O)Cl NHR²-Y as a A-CR²R^(2a)C(O)-NR²-Y substituent 21 A-CR²R^(2a)C(O)Cl a secondary NH A-CR²R^(2a)C(O)-Y as part of a ring or chain 22 A-SO₂Cl NHR²-Y as a A-SO₂-NR²-Y substituent 23 A-SO₂Cl a secondary NH A-SO₂-Y as part of a ring or chain 24 A-CR²R^(2a)SO₂Cl NHR²-Y as a A-CR²R^(2a)SO₂-NR²-Y substituent 25 A-CR²R^(2a)SO₂Cl a secondary NH A-CR²R^(2a)SO₂-Y as part of a ring or chain

[0227] The chemistry of Table A can be carried out in aprotic solvents such as a chlorocarbon, pyridine, benzene or toluene, at temperatures ranging from −20° C. to the reflux point of the solvent and with or without a trialkylamine base. TABLE B Preparation of ketone linkages between A and B. then the reactive to give the Rxn. substituent of following product No. if A contains: Y is: A-X-Y: 1 A-C(O)Cl BrMg-Y A-C(O)-Y 2 A-CR²R^(2a)C(O)Cl BrMg-Y A-CR²R2^(2a)C(O)-Y 3 A-C(O)Cl BrMgCR²R^(2a)-Y A-C(O)CR²R^(2a)-Y 4 A-CR²R^(2a)C(O)Cl BrMgCR²R^(2a)-Y A-CR²R^(2a)C(O)CR²R^(2a)- y

[0228] The coupling chemistry of Table B can be carried out by a variety of methods. The Grignard reagent required for Y is prepared from a halogen analog of Y in dry ether, dimethoxyethane or tetrahydrofuran at 0° C. to the reflux point of the solvent. This Grignard reagent can be reacted directly under very controlled conditions, that is low temeprature (−20° C. or lower) and with a large excess of acid chloride or with catalytic or stoichiometric copper bromide-dimethyl sulfide complex in dimethyl sulfide as a solvent or with a variant thereof. Other methods available include transforming the Grignard reagent to the cadmium reagent and coupling according to the procedure of Carson and Prout (Org. Syn. Col. Vol. 3 (1955) 601) or a coupling mediated by Fe(acac)₃ according to Fiandanese et al. (Tetrahedron Lett., (1984) 4805), or a coupling mediated by manganese (II) catalysis (Cahiez and Laboue, Tetrahedron Lett., 33(31), (1992) 4437). TABLE C Preparation of ether and thioether linkages between A and B then the reactive to give the Rxn. substituent of following No. if A contains: Y is: product A-X-Y: 1 A-OH Br-Y A-O-Y 2 A-CR²R^(2a)-OH Br-Y A-CR²R^(2a)O-Y 3 A-OH Br-CR²R^(2a)-Y A-OCR²R^(2a)-Y 4 A-SH Br-Y A-S-Y 5 A-CR²R^(2a)-SH Br-Y A-CR²R^(2a)S-Y 6 A-SH Br-CR²R^(2a)-Y A-SCR²R^(2a)-Y

[0229] The ether and thioether linkages of Table C can be prepared by reacting the two components in a polar aprotic solvent such as acetone, dimethylformamide or dimethylsulfoxide in the presence of a base such as potassium carbonate, sodium hydride or potassium t-butoxide at temperature ranging from ambient temperature to the reflux point of the solvent used. TABLE D Preparation of -SO- and -SO2- linkages from thioethers of Table 3. and it is oxidized and it is oxidized with m-chloroper- with Alumina (wet)/ benzoic acid (Satoh if the Oxone (Greenhaigh, et al., Chem. Lett. Rxn. starting Synlett, (1992) 235) (1992) 381), the No. material is: the product is: product is: 1 A-S-Y A-S(O)-Y A-SO₂-Y 2 A-CR²R^(2a)S-Y A-CR²R^(2a)S(O)-Y A-CR²R^(2a)SO₂-Y 3 A-SCR²R^(2a)-Y A-S(O)CR²R^(2a)-Y A-SO₂CR²R^(2a)-Y

[0230] The thioethers of Table C serve as a convenient starting material for the preparation of the sulfoxide and sulfone analogs of Table D. A combination of wet alumina and oxone can provide a reliable reagent for the oxidation of the thioether to the sulfoxide while m-chloroperbenzoic acid oxidation will give the sulfone. TABLE E Methods of Preparing Group E Rxn Q D is to be then a transformation that may be used is: 1 —CN —C(═NH)NH2

2 —CN —CH2NH2

3 —CO2H —CH2NH2

4 —CO2H —NH2

[0231] In Table E several methods of transforming a functional group Q into group D of Formula I are shown. While not all possible functional groups for Q and D are listed and the synthetic methods suggested are not comprehensive, Table E is meant to illustrate strategies and transformations available to a practitioner skilled in the art of organic synthesis for preparing compounds of Formula I. In reaction 1 of Table E the transformation of a nitrile into an amidine by the Pinner methodology is shown; in reaction 2 the direct reduction of a nitrile by a hydride reducing agent to a methylene amine is illustrated. In reaction 3, the utility of a carboxylic acid, which may be readily derived from its ester or a nitrile if necessary, in the preparation of a methylene amine is shown. This synthetic route is exceptionally flexible because of the several stable intermediates prepared en route to the final product. As outlined, formation of an activated analog, such as the mixed anhydride, allows for the mild reduction of the acid to the methylene alcohol, this may in turn be transformed into a leaving group by sulfonylation or halogenation or protected with a suitable protecting group to be transformed later in the synthesis as the chemistry demands. Once the methylene alcohol is so activated, displacement by an efficient nitrogen nucleophile, such as azide anion, can again provide another suitably stable analog, —the methylene azide—which may be used as a protected form of the methylene amine or transformed directly into the methylene amine group by reduction. Reaction 4 addresses the problem of appending the amine functionality directly through a bond to group E of Formula I. Once again, the carboxylic acid provides a convenient entre into this selection for group D. The well-know Curtius rearrangement is illustrated here; an activated acid analog can be used to form an acyl azide which upon thermal decomposition is rearranged to the corresponding isocyanate. The isocyanate intermediate may then be captured as a stable carbamate by the addition of a suitable alcohol and further heating. This carbamate can be used as a stable protecting group for the amine or cleaved directly to the desired D. Alternatively, it may be convenient to quench the isocyanate intermediate with water to give the amine directly.

[0232] One diastereomer of a compound of Formula I may display superior activity compared with the others. Thus, the following stereochemistries are considered to be a part of the present invention.

[0233] When required, separation of the racemic material can be achieved by HPLC using a chiral column or by a resolution using a resolving agent such as camphonic chloride as in Steven D. Young, et al, Antimicrobial Agents and Chemotheraphy, 1995, 2602-2605. A chiral compound of Formula I may also be directly synthesized using a chiral catalyst or a chiral ligand, e.g., Andrew S. Thompson, et al, Tet. lett. 1995, 36, 8937-8940).

[0234] Other features of the invention will become apparent in the course of the following descriptions of exemplary embodiments which are given for illustration of the invention and are not intended to be limiting thereof.

EXAMPLES Examples 1 and 2 1-(3-Amidinophenyl)-5-[[(2′-methylsulfonyl-[1,1′]-biphen-4-yl)-aminocarbonyl]-3-trifluoromethyl-pyrazoline and 1-(3-aminomethylphenyl)-5-[[(2′-methylsulfonyl-[1,1′]-biphen-4-yl)-aminocarbonyl]-3-trifluoromethyl-pyrazoline

[0235] Part A:

[0236] To a methanolic solution containing meta-cyanophenyl-hydrazine (2 g, 15.03 mmol) was added trifluoromethylacetaldehyde hydrate (1.74 g, 15.03 mmol). The reaction mixture was heated to gentle reflux overnight. Methanol was stripped off to afford yellow crystals of pure hydrazone (2.99 g, 93%). ¹HNMR (CDCl₃)δ: 10.10 (bs, 1H), 7.33 (m, 2H), 7.10 (m, 2H) ppm; ESI (-ve) mass spectrum analysis m/z (relative intensity) 212 (M−H, 100).

[0237] Part B:

[0238] NCS (1.02 g, 7.69 mmol) was added to a DMF (25 mL) solution of the compound prepared in part A (1.64 g, 7.69 mmol). The reaction mixture was stirred at room temperature over night, quenched with water (500 mL) and organics extracted with ethyl acetate (2×100 mL) dried (MgSO₄) and evaporated to a reddish brown oil. The oil was redissolved in chloroform (25 mL) and to this solution was added ethyl acrylate (10 mL) followed by slow addition of triethylamine (0.81 mL, 5.75 mmol.). The reaction mixture was refluxed for 18 h cooled and quenched with dil. hydrochloric acid (1N, 20 mL). The organic layer was separated and evaporated to an oil. Chromatography on silica gel (7:3, Hexane:ethylacetate) afforded a colorless oil which solidified on standing (1.5 g, 62%). ¹HNMR(CDCl₃)δ: 7.40-7.22 (m, 4H), 4.89 (dd, J=6.2 and 13.4 Hz, 1H), 4.24 (q, 2H), 3.63-3.50 (dd, J=1.9 and 13.2 Hz, 1H), 3.38 (dd, J=1.9 and 14 Hz, 1H), 1.23 (t, 3H) ppm; ESI mass spectrum analysis m/z (relative intensity) 312 (M+H, 100).

[0239] Part C:

[0240] The product from part B was treated with 2′-methylsulfonyl-4-amino-(1,1′]biphenyl under Weinreb conditions (trimethylaluminum in dichloromethane) to afford pure coupled product (oil) after silica gel column chromatography (hexane:ethyl acetate 7:3). ¹HNMR(CDCl₃)δ: 8.40 (bs, 1H), 8.17 (dd, J=1.1 and 7.8 Hz, 1H), 7.65-7.25 (m, 11H), 4.90 (m, 1H), 3.78 (m, 1H), 3.38 (dd, J=1.5 and 8.1 Hz, 1H), 2.69 s, 3H); ESI (-ve) mass spectrum analysis m/z (rel. intensity) 511 (M—H, 100).

[0241] Part D:

[0242] The product from part C was subjected to the Pinner amidine reaction sequence (HCl/MeOH followed by ammonium carbonate in methanol), purified via standard HPLC purification, lyophilization to afford (40% yield) of Example 1 as colorless crystals. ¹HNMR(DMSO₆)δ: 9.36 (bs, 1.5H), 9.00 (bs, 1.5 Hz), 8.06 (d, J=7.7 Hz, 1H), 7.53-7.78 (m, 6H), 7.35 (d, J=8.1 Hz, 3H), 7.27 (d, J=8.0 Hz, 1H), 7.17 (d, J=8.5 Hz, 1H), 5.33 (dd, J=6.2 and 13.2 Hz, 1H), 3.76 (t, 1H), 3.40 (d, J=3.1 Hz, 1H), 2.84 (s, 3H) ppm; ESI (+ve) mass spectum analysis m/z (relative intensity) 530 (M+H, 100).

[0243] Additionally, the compound form Part C was subjected to reduction using 10% Pd/C in an acidic medium (methanol/acetic acid). Purification via standard HPLC techniques and lyophilization afforded the benzylamine (10% yield). ¹HNMR(DMSO₆)δ: 8.07 (bs, 2H), 8.01 (d, J=8 Hz, 1H), 7.70 (m, 1H), 7.59 (m, 3H), 7.28 (m, 4H), 6.95 (d, J=8 Hz, 1H), 6.83 (dd, J=1/5 and 8 Hz, 1H), 6.40 (bs, 2H), 5.22 (dd, J=6.5 and 13 Hz, 1H), 4.00 (m, 1H), 3.71 (m, 1H), 3.34 (dd, J=1.5 and 8 Hz, 1H), 2.84 (s, 3H) ppm; ESI mass spectrum analysis m/z (relative intensity) 517 (M+H, 100).

[0244] The following tables contain representative examples of the present invention. Each entry in each table is intended to be paired with each formulae at the start of the table. For example, in Table 1, example 1 is intended to be paired with each of formulae a-ttt and in Table 2, example 1 is intended to be paired with each of formulae a-ss.

[0245] The following groups are intended for group A in the following tables.

TABLE 1

Ex # R^(1c) A B 1 CH₃ phenyl 2-(aminosulfonyl)phenyl 2 CH₃ phenyl 2-(methylaminosulfonyl)phenyl 3 CH₃ phenyl 1-pyrrolidinocarbonyl 4 CH₃ phenyl 2-(methylsulfonyl) phenyl 5 CH₃ phenyl 4-morpholino 6 CH₃ phenyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 7 CH₃ phenyl 4-morpholinocarbonyl 8 CH₃ phenyl 2-methyl-1-imidazolyl 9 CH₃ phenyl 5-methyl-1-imidazolyl 10 CH₃ phenyl 2-methylsulfonyl-1-imidazolyl 11 CH₃ 2-pyridyl 2-(aminosulfonyl)phenyl 12 CH₃ 2-pyridyl 2-(methylaminosulfonyl)phenyl 13 CH₃ 2-pyridyl 1-pyrrolidinocarbonyl 14 CH₃ 2-pyridyl 2-(methylsulfonyl)phenyl 15 CH₃ 2-pyridyl 4-morpholino 16 CH₃ 2-pyridyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 17 CH₃ 2-pyridyl 4-morpholinocarbonyl 18 CH₃ 2-pyridyl 2-methyl-1-imidazolyl 19 CH₃ 2-pyridyl 5-methyl-1-imidazolyl 20 CH₃ 2-pyridyl 2-methylsulfonyl-1-imidazolyl 21 CH₃ 3-pyridyl 2-(aminosulfonyl)phenyl 22 CH₃ 3-pyridyl 2-(methylaminosulfonyl)phenyl 23 CH₃ 3-pyridyl 1-pyrrolidinocarbonyl 24 CH₃ 3-pyridyl 2-(methylsulfonyl)phenyl 25 CH₃ 3-pyridyl 4-morpholino 26 CH₃ 3-pyridyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 27 CH₃ 3-pyridyl 4-morpholinocarbonyl 28 CH₃ 3-pyridyl 2-methyl-1-imidazolyl 29 CH₃ 3-pyridyl 5-methyl-1-imidazolyl 30 CH₃ 3-pyridyl 2-methylsulfonyl-1-imidazolyl 31 CH₃ 2-pyrimidyl 2-(aminosulfonyl)phenyl 32 CH₃ 2-pyrimidyl 2-(methylaminosulfonyl)phenyl 33 CH₃ 2-pyrimidyl 1-pyrrolidinocarbonyl 34 CH₃ 2-pyrimidyl 2-(methylsulfonyl)phenyl 35 CH₃ 2-pyrimidyl 4-morpholino 36 CH₃ 2-pyrimidyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 37 CH₃ 2-pyrimidyl 4-morpholinocarbonyl 38 CH₃ 2-pyrimidyl 2-methyl-1-imidazolyl 39 CH₃ 2-pyrimidyl 5-methyl-1-imidazolyl 40 CH₃ 2-pyrimidyl 2-methylsulfonyl-1-imidazolyl 41 CH₃ 5-pyrimidyl 2-(aminosulfonyl)phenyl 42 CH₃ 5-pyrimidyl 2-(methylaminosulfonyl)phenyl 43 CH₃ 5-pyrimidyl 1-pyrrolidinocarboriyl 44 CH₃ 5-pyrimidyl 2-(methylsulfonyl)phenyl 45 CH₃ 5-pyrimidyl 4-morpholino 46 CH₃ 5-pyrimidyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 47 CH₃ 5-pyrimidyl 4-morpholinocarbonyl 48 CH₃ 5-pyrimidyl 2-methyl-1-imidazolyl 49 CH₃ 5-pyrimidyl 5-methyl-1-imidazolyl 50 CH₃ 5-pyrimidyl 2-methylsulfonyl-1-imidazolyl 51 CH₃ 2-Cl-phenyl 2-(aminosulfonyl)phenyl 52 CH₃ 2-Cl-phenyl 2-(methylaminosulfonyl)phenyl 53 CH₃ 2-Cl-phenyl 1-pyrrolidinocarboriyl 54 CH₃ 2-Cl-phenyl 2-(methylsulfonyl)phenyl 55 CH₃ 2-Cl-phenyl 4-morpholino 56 CH₃ 2-Cl-phenyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 57 CH₃ 2-Cl-phenyl 4-morpholinocarbonyl 58 CH₃ 2-Cl-phenyl 2-methyl-1-imidazolyl 59 CH₃ 2-Cl-phenyl 5-methyl-1-imidazolyl 60 CH₃ 2-Cl-phenyl 2-methylsulfonyl-1-imidazolyl 61 CH₃ 2-F-phenyl 2-(aminosulfonyl)phenyl 62 CH₃ 2-F-phenyl 2-(methylaminosulfonyl)phenyl 63 CH₃ 2-F-phenyl 1-pyrrolidinocarbonyl 64 CH₃ 2-F-phenyl 2-(methylsulfonyl)phenyl 65 CH₃ 2-F-phenyl 4-morpholino 66 CH₃ 2-F-phenyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 67 CH₃ 2-F-phenyl 4-morpholinocarbonyl 68 CH₃ 2-F-phenyl 2-methyl-1-imidazolyl 69 CH₃ 2-F-phenyl 5-methyl-1-imidazolyl 70 CH₃ 2-F-phenyl 2-methylsulfonyl-1-imidazolyl 71 CH₃ 2,6-diF-phenyl 2-(aminosulfonyl)phenyl 72 CH₃ 2,6-diF-phenyl 2-(methylaminosulfonyl)phenyl 73 CH₃ 2,6-diF-phenyl 1-pyrrolidinocarbonyl 74 CH₃ 2,6-diF-phenyl 2-(methylsulfonyl)phenyl 75 CH₃ 2,6-diF-phenyl 4-morpholino 76 CH₃ 2,6-diF-phenyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 77 CH₃ 2,6-diF-phenyl 4-morpholinocarbonyl 78 CH₃ 2,6-diF-phenyl 2-methyl-1-imidazolyl 79 CH₃ 2,6-diF-phenyl 5-methyl-1-imidazolyl 80 CH₃ 2,6-diF-phenyl 2-methylsulfonyl-1-imidazolyl 81 CH₂CH₃ phenyl 2-(aminosulforiyl)phenyl 82 CH₂CH₃ phenyl 2-(methylaminosulfonyl)phenyl 83 CH₂CH₃ phenyl 1-pyrrolidinocarbonyl 84 CH₂CH₃ phenyl 2-(methylsulfonyl)phenyl 85 CH₂CH₃ phenyl 4-morpholino 86 CH₂CH₃ phenyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 87 CH₂CH₃ phenyl 4-morpholinocarbonyl 88 CH₂CH₃ phenyl 2-methyl-1-imidazolyl 89 CH₂CH₃ phenyl 5-methyl-1-imidazolyl 90 CH₂CH₃ phenyl 2-methylsulfonyl-1-imidazolyl 91 CH₂CH₃ 2-pyridyl 2-(aminosulfonyl)phenyl 92 CH₂CH₃ 2-pyridyl 2-(methylaminosulfonyl)phenyl 93 CH₂CH₃ 2-pyridyl 1-pyrrolidinocarbonyl 94 CH₂CH₃ 2-pyridyl 2-(methylsulfonyl)phenyl 95 CH₂CH₃ 2-pyridyl 4-morpholino 96 CH₂CH₃ 2-pyridyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 97 CH₂CH₃ 2-pyridyl 4-morpholinocarbonyl 98 CH₂CH₃ 2-pyridyl 2-methyl-1-imidazolyl 99 CH₂CH₃ 2-pyridyl 5-methyl-1-imidazolyl 100 CH₂CH₃ 2-pyridyl 2-methylsulfonyl-1-imidazolyl 101 CH₂CH₃ 3-pyridyl 2-(aminosulfonyl)phenyl 102 CH₂CH₃ 3-pyridyl 2-(methylaminosulfonyl) phenyit 103 CH₂CH₃ 3-pyridyl 1-pyrrolidinocarbonyl 104 CH₂CH₃ 3-pyridyl 2-(methylsulfonyl)phenyl 105 CH₂CH₃ 3-pyridyl 4-morpholino 106 CH₂CH₃ 3-pyridyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 107 CH₂CH₃ 3-pyridyl 4-morpholinocarbonyl 108 CH₂CH₃ 3-pyridyl 2-methyl-1-imidazolyl 109 CH₂CH₃ 3-pyridyl 5-methyl-1-imidazolyl 110 CH₂CH₃ 3-pyridyl 2-methylsulfonyl-1-imidazolyl 111 CH₂CH₃ 2-pyrimidyl 2-(aminosulfonyl)phenyl 112 CH₂CH₃ 2-pyrimidyl 2-(methylaminosulfonyl)phenyl 113 CH₂CH₃ 2-pyrimidyl 1-pyrrolidinocarbonyl 114 CH₂CH₃ 2-pyrimidyl 2-(methylsulfonyl)phenyl 115 CH₂CH₃ 2-pyrimidyl 4-morpholino 116 CH₂CH₃ 2-pyrimidyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 117 CH₂CH₃ 2-pyrimidyl 4-morpholinocarbonyl 118 CH₂CH₃ 2-pyrimidyl 2-methyl-1-imidazolyl 119 CH₂CH₃ 2-pyrimidyl 5-methyl-1-imidazolyl 120 CH₂CH₃ 2-pyrimidyl 2-methylsulfonyl-1-imidazolyl 121 CH₂CH₃ 5-pyrimidyl 2-(aminosulfonyl)phenyl 122 CH₂CH₃ 5-pyrimidyl 2-(methylaminosulfonyl)phenyl 123 CH₂CH₃ 5-pyrimidyl 1-pyrrolidinocarbonyl 124 CH₂CH₃ 5-pyrimidyl 2-(methylsulfonyl)phenyl 125 CH₂CH₃ 5-pyrimidyl 4-morpholino 126 CH₂CH₃ 5-pyrimidyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 127 CH₂CH₃ 5-pyrimidyl 4-morpholinocarbonyl 128 CH₂CH₃ 5-pyrimidyl 2-methyl-1-imidazolyl 129 CH₂CH₃ 5-pyrimidyl 5-methyl-1-imidazolyl 130 CH₂CH₃ 5-pyrimidyl 2-methylsulfonyl-1-imidazolyl 131 CH₂CH₃ 2-Cl-phenyl 2-(aminosulfonyl)phenyl 132 CH₂CH₃ 2-Cl-phenyl 2-(methylaminosulfonyl)phenyl 133 CH₂CH₃ 2-Cl-phenyl 1-pyrrolidinocarbonyl 134 CH₂CH₃ 2-Cl-phenyl 2-(methylsulfonyl)phenyl 135 CH₂CH₃ 2-Cl-phenyl 4-morpholino 136 CH₂CH₃ 2-Cl-phenyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 137 CH₂CH₃ 2-Cl-phenyl 4-morpholinocarbonyl 138 CH₂CH₃ 2-Cl-phenyl 2-methyl-1-imidazolyl 139 CH₂CH₃ 2-Cl-phenyl 5-methyl-1-imidazolyl 140 CH₂CH₃ 2-Cl-phenyl 2-methylsulfonyl-1-imidazolyl 141 CH₂CH₃ 2-F-phenyl 2-(aminosulfonyl) phenyl 142 CH₂CH₃ 2-F-phenyl 2-(methylaminosulfonyl) phenyl 143 CH₂CH₃ 2-F-phenyl 1-pyrrolidinocarbonyl 144 CH₂CH₃ 2-F-phenyl 2-(methylsulfonyl)phenyl 145 CH₂CH₃ 2-F-phenyl 4-morpholino 146 CH₂CH₃ 2-F-phenyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 147 CH₂CH₃ 2-F-phenyl 4-morpholinocarbonyl 148 CH₂CH₃ 2-F-phenyl 2-methyl-1-imidazolyl 149 CH₂CH₃ 2-F-phenyl 5-methyl-1-imidazolyl 150 CH₂CH₃ 2-F-phenyl 2-methylsulfonyl-1-imidazolyl 151 CH₂CH₃ 2,6-diF-phenyl 2-(aminosulfonyl)phenyl 152 CH₂CH₃ 2,6-diF-phenyl 2-(methylaminosulfonyl)phenyl 153 CH₂CH₃ 2,6-diF-phenyl 1-pyrrolidinocarbonyl 154 CH₂CH₃ 2,6-diF-phenyl 2-(methylsulfonyl)phenyl 155 CH₂CH₃ 2,6-diF-phenyl 4-inorpholino 156 CH₂CH₃ 2,6-diF-phenyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 157 CH₂CH₃ 2,6-diF-phenyl 4-morpholinocarbonyl 158 CH₂CH₃ 2,6-diF-phenyl 2-methyl-1-imidazolyl 159 CH₂CH₃ 2,6-diF-phenyl 5-methyl-1-imidazolyl 160 CH₂CH₃ 2,6-diF-phenyl 2-methylsulfonyl-1-imidazolyl 161 CF₃ phenyl 2-(aminosulfonyl)phenyl 162 CF₃ phenyl 2-(methylaminosulfonyl)phenyl 163 CF₃ phenyl 1-pyrrolidinocarbonyl 164 CF₃ phenyl 2-(methylsulfonyl)phenyl 165 CF₃ phenyl 4-morpholino 166 CF₃ phenyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 167 CF₃ phenyl 4-morpholinocarbonyl 168 CF₃ phenyl 2-methyl-1-imidazolyl 169 CF₃ phenyl 5-methyl-1-imidazolyl 170 CF₃ phenyl 2-methylsulfonyl-1-imidazolyl 171 CF₃ 2-pyridyl 2-(aminosulfonyl)phenyl 172 CF₃ 2-pyridyl 2-(methylaminosulfonyl)phenyl 173 CF₃ 2-pyridyl 1-pyrrolidinocarbonyl 174 CF₃ 2-pyridyl 2-(methylsulfonyl)phenyl 175 CF₃ 2-pyridyl 4-morpholino 176 CF₃ 2-pyridyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 177 CF₃ 2-pyridyl 4-morpholinocarbonyl 178 CF₃ 2-pyridyl 2-methyl-1-imidazolyl 179 CF₃ 2-pyridyl 5-methyl-1-imidazolyl 180 CF₃ 2-pyridyl 2-methylsulfonyl-1-imidazolyl 181 CF₃ 3-pyridyl 2-(aminosulfonyl)phenyl 182 CF₃ 3-pyridyl 2-(methylaminosulfonyl)phenyl 183 CF₃ 3-pyridyl l-pyrrolidinocarbonyl 184 CF₃ 3-pyridyl 2-(methylsulfonyl)phenyl 185 CF₃ 3-pyridyl 4-morpholino 186 CF₃ 3-pyridyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 187 CF₃ 3-pyridyl 4-morpholinocarbonyl 188 CF₃ 3-pyridyl 2-methyl-1-imidazolyl 189 CF₃ 3-pyridyl 5-methyl-1-imidazolyl 190 CF₃ 3-pyridyl 2-methylsulfonyl-1-imidazolyl 191 CF₃ 2-pyrimidyl 2-(aminosulfonyl)phenyl 192 CF₃ 2-pyrimidyl 2-(methylaminosulfonyl) phenyl 193 CF₃ 2-pyrimidyl 1-pyrrolidinocarbonyl 194 CF₃ 2-pyrimidyl 2-(methylsulfonyl)phenyl 195 CF₃ 2-pyrimidyl 4-morpholino 196 CF₃ 2-pyrimidyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 197 CF₃ 2-pyrimidyl 4-morpholinocarbonyl 198 CF₃ 2-pyrimidyl 2-methyl-1-imidazolyl 199 CF₃ 2-pyrimidyl 5-methyl-1-imidazolyl 200 CF₃ 2-pyrimidyl 2-methylsulfonyl-1-imidazolyl 201 CF₃ 5-pyrimidyl 2-(aminosulfonyl)phenyl 202 CF₃ 5-pyrimidyl 2-(methylaminosulfonyl)phenyl 203 CF₃ 5-pyrimidyl 1-pyrrolidinocarbonyl 204 CF₃ 5-pyrimidyl 2-(methylsulfonyl)phenyl 205 CF₃ 5-pyrimidyl 4-morpholino 206 CF₃ 5-pyrimidyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 207 CF₃ 5-pyrimidyl 4-morpholinocarbonyl 208 CF₃ 5-pyrimidyl 2-methyl-1-imidazolyl 209 CF₃ 5-pyrimidyl 5-methyl-1-imidazolyl 210 CF₃ 5-pyrimidyl 2-methylsulfonyl-1-imidazolyl 211 CF₃ 2-Cl-phenyl 2-(aminosulfonyl)phenyl 212 CF₃ 2-Cl-phenyl 2-(methylaminosulfonyl)phenyl 213 CF₃ 2-Cl-phenyl 1-pyrrolidinocarbonyl 214 CF₃ 2-Cl-phenyl 2-(methylsulfonyl)phenyl 215 CF₃ 2-Cl-phenyl 4-morpholino 216 CF₃ 2-Cl-phenyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 217 CF₃ 2-Cl-phenyl 4-morpholinocarbonyl 218 CF₃ 2-Cl-phenyl 2-methyl-1-imidazolyl 219 CF₃ 2-Cl-phenyl 5-methyl-1-imidazolyl 220 CF₃ 2-Cl-phenyl 2-methylsulfonyl-1-imidazolyl 221 CF₃ 2-F-phenyl 2-(aminosulfonyl)phenyl 222 CF₃ 2-F-phenyl 2-(methylaminosulfonyl)phenyl 223 CF₃ 2-F-phenyl 1-pyrrolidinocarbonyl 224 CF₃ 2-F-phenyl 2-(methylsulfonyl)phenyl 225 CF₃ 2-F-phenyl 4-morpholino 226 CF₃ 2-F-phenyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 227 CF₃ 2-F-phenyl 4-morpholinocarbonyl 228 CF₃ 2-F-phenyl 2-methyl-1-imidazolyl 229 CF₃ 2-F-phenyl 5-methyl-1-imidazolyl 230 CF₃ 2-F-phenyl 2-methylsulfonyl-1-imidazolyl 231 CF₃ 2,6-diF-phenyl 2-(aminosulfonyl)phenyl 232 CF₃ 2,6-diF-phenyl 2-(methylaminosulfonyl)phenyl 233 CF₃ 2,6-diF-phenyl 1-pyrrolidinocarbonyl 234 CF₃ 2,6-diF-phenyl 2-(methylsulfonyl)phenyl 235 CF₃ 2,6-diF-phenyl 4-morpholino 236 CF₃ 2,6-diF-phenyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 237 CF₃ 2,6-diF-phenyl 4-morpholinocarbonyl 238 CF₃ 2,6-diF-phenyll 2-methyl-1-imidazolyl 239 CF₃ 2,6-diF-phenyl 5-methyl-1-imidazolyl 240 CF₃ 2,6-diF-phenyl 2-methylsulfonyl-1-imidazolyl 241 SCH₃ phenyl 2-(aminosulfonyl)phenyl 242 SCH₃ phenyl 2-(methylaminosulfonyl)phenyl 243 SCH₃ phenyl 1-pyrrolidinocarbonyl 244 SCH₃ phenyl 2-(methylsulfonyl)phenyl 245 SCH₃ phenyl 4-morpholino 246 SCH₃ phenyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 247 SCH₃ phenyl 4-morpholinocarbonyl 248 SCH₃ phenyl 2-methyl-1-imidazolyl 249 SCH₃ phenyl 5-methyl-1-imidazolyl 250 SCH₃ phenyl 2-methylsulfonyl-1-imidazolyl 251 SCH₃ 2-pyridyl 2-(aminosulfonyl)phenyl 252 SCH₃ 2-pyridyl 2-(methylaminosulfonyl)phenyl 253 SCH₃ 2-pyridyl 1-pyrrolidinocarbonyl 254 SCH₃ 2-pyridyl 2-(methylsulfonyl)phenyl 255 SCH₃ 2-pyridyl 4-morpholino 256 SCH₃ 2-pyridyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 257 SCH₃ 2-pyridyl 4-morpholinocarbonyl 258 SCH₃ 2-pyridyl 2-methyl-1-imidazolyl 259 SCH₃ 2-pyridyl 5-methyl-1-imidazolyl 260 SCH₃ 2-pyridyl 2-methylsulfonyl-1-imidazolyl 261 SCH₃ 3-pyridyl 2-(aminosulfonyl)phenyl 262 SCH₃ 3-pyridyl 2-(methylaminosulfonyl)phenyl 263 SCH₃ 3-pyridyl 1-pyrrolidinocarbonyl 264 SCH₃ 3-pyridyl 2-(methylsulfonyl)phenyl 265 SCH₃ 3-pyridyl 4-morpholino 266 SCH₃ 3-pyridyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 267 SCH₃ 3-pyridyl 4-morpholinocarbonyl 268 SCH₃ 3-pyridyl 2-methyl-1-imidazolyl 269 SCH₃ 3-pyridyl 5-methyl-1-imidazolyl 270 SCH₃ 3-pyridyl 2-methylsulfonyl-1-imidazolyl 271 SCH₃ 2-pyrimidyl 2-(aminosulfonyl)phenyl 272 SCH₃ 2-pyrimidyl 2-(methylaminosulfonyl)phenyl 273 SCH₃ 2-pyrimidyl 1-pyrrolidinocarbonyl 274 SCH₃ 2-pyrimidyl 2-(methylsulfonyl)phenyl 275 SCH₃ 2-pyrimidyl 4-morpholino 276 SCH₃ 2-pyrimidyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 277 SCH₃ 2-pyrimidyl 4-morpholinocarbonyl 278 SCH₃ 2-pyrimidyl 2-methyl-1-imidazolyl 279 SCH₃ 2-pyrimidyl 5-methyl-1-imidazolyl 280 SCH₃ 2-pyrimidyl 2-methylsulfonyl-1-imidazolyl 281 SCH₃ 5-pyrimidyl 2-(aminosulfonyl)phenyl 282 SCH₃ 5-pyrimidyl 2-(methylaminosulffonyl)phenyl 283 SCH₃ 5-pyrimidyl 1-pyrrolidinocarbonyl 284 SCH₃ 5-pyrimidyl 2-(methylsulfonyl)phenyl 285 SCH₃ 5-pyrimidyl 4-morpholino 286 SCH₃ 5-pyrimidyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 287 SCH₃ 5-pyrimidyl 4-morpholinocarbonyl 288 SCH₃ 5-pyrimidyl 2-methyl-1-imidazolyl 289 SCH₃ 5-pyrimidyl 5-methyl-1-imidazolyl 290 SCH₃ 5-pyrimidyl 2-methylsulfonyl-1-imidazolyl 291 SCH₃ 2-Cl-phenyl 2-(aminosulfonyl)phenyl 292 SCH₃ 2-Cl-phenyl 2-(methylaminosulfonyl)phenyl 293 SCH₃ 2-Cl-phenyl 1-pyrrolidinocarbonyl 294 SCH₃ 2-Cl-phenyl 2-(methylsulfonyl)phenyl 295 SCH₃ 2-Cl-phenyl 4-morpholino 296 SCH₃ 2-Cl-phenyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 297 SCH₃ 2-Cl-phenyl 4-morpholinocarbonyl 298 SCH₃ 2-Cl-phenyl 2-methyl-1-imidazolyl 299 SCH₃ 2-Cl-phenyl 5-methyl-1-imidazolyl 300 SCH₃ 2-Cl-phenyl 2-methylsulfonyl-1-imidazolyl 301 SCH₃ 2-F-phenyl 2-(aminosulfonyl)phenyl 302 SCH₃ 2-F-phenyl 2-(methylaminosulfonyl)phenyl 303 SCH₃ 2-F-phenyl 1-pyrrolidinocarbonyl 304 SCH₃ 2-F-phenyl 2-(methylsulfonyl )phenyl 305 SCH₃ 2-F-phenyl 4-morpholino 306 SCH₃ 2-F-phenyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 307 SCH₃ 2-F-phenyl 4-morpholinocarbonyl 308 SCH₃ 2-F-phenyl 2-methyl-1-imidazolyl 309 SCH₃ 2-F-phenyl 5-methyl-1-imidazolyl 310 SCH₃ 2-F-phenyl 2-methylsulfonyl-1-imidazolyl 311 SCH₃ 2,6-diF-phenyl 2-(aminosulfonyl)phenyl 312 SCH₃ 2,6-diF-phenyl 2-(methylaminosulfonyl)phenyl 313 SCH₃ 2,6-diF-phenyl 1-pyrrolidinocarbonyl 314 SCH₃ 2,6-diF-phenyl 2-(methylsulfonyl)phenyl 315 SCH₃ 2,6-diF-phenyl 4-morpholino 316 SCH₃ 2,6-diF-phenyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 317 SCH₃ 2,6-diF-phenyl 4-morpholinocarbonyl 318 SCH₃ 2,6-diF-phenyl 2-methyl-1-imidazolyl 319 SCH₃ 2,6-diF-phenyl 5-methyl-1-imidazolyl 320 SCH₃ 2,6-diF-phenyl 2-methylsulfonyl-1-imidazolyl 321 SOCH₃ phenyl 2-(aminosulfonyl)phenyl 322 SOCH₃ phenyl 2-(methylaminosulfonyl )phenyl 323 SOCH₃ phenyl 1-pyrrolidinocarbonyl 324 SOCH₃ phenyl 2-(methylsulfonyl)phenyl 325 SOCH₃ phenyl 4-morpholino 326 SOCH₃ phenyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 327 SOCH₃ phenyl 4-morpholinocarbonyl 328 SOCH₃ phenyl 2-methyl-1-imidazolyl 329 SOCH₃ phenyl 5-methyl-1-imidazolyl 330 SOCH₃ phenyl 2-methylsulfonyl-1-imidazolyl 331 SOCH₃ 2-pyridyl 2-(aminosulfonyl)phenyl 332 SOCH₃ 2-pyridyl 2-(methylaminosulfonyl)phenyl 333 SOCH₃ 2-pyridyl 1-pyrrolidinocarbonyl 334 SOCH₃ 2-pyridyl 2-(methylsulfonyl)phenyl 335 SOCH₃ 2-pyridyl 4-morpholino 336 SOCH₃ 2-pyridyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 337 SOCH₃ 2-pyridyl 4-morpholinocarbonyl 338 SOCH₃ 2-pyridyl 2-methyl-1-imidazolyl 339 SOCH₃ 2-pyridyl 5-methyl-1-imidazolyl 340 SOCH₃ 2-pyridyl 2-methylsulfonyl-1-imidazolyl 341 SOCH₃ 3-pyridyl 2-(aminosulfonyl)phenyl 342 SOCH₃ 3-pyridyl 2-(methylaminosulfonyl)phenyl 343 SOCH₃ 3-pyridyl 1-pyrrolidinocarbonyl 344 SOCH₃ 3-pyridyl 2-(methylsulfonyl)phenyl 345 SOCH₃ 3-pyridyl 4-morpholino 346 SOCH₃ 3-pyridyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 347 SOCH₃ 3-pyridyl 4-morpholinocarbonyl 348 SOCH₃ 3-pyridyl 2-methyl-1-imidazolyl 349 SOCH₃ 3-pyridyl 5-methyl-1-imidazolyl 350 SOCH₃ 3-pyridyl 2-methylsulfonyl-1-imidazolyl 351 SOCH₃ 2-pyrimidyl 2-(aminosulfonyl)phenyl 352 SOCH₃ 2-pyrimidyl 2-(methylaminosulfonyl)phenyl 353 SOCH₃ 2-pyrimidyl 1-pyrrolidinocarbonyl 354 SOCH₃ 2-pyrimidyl 2-(methylsulfonyl)phenyl 355 SOCH₃ 2-pyrimidyl 4-morpholino 356 SOCH₃ 2-pyrimidyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 357 SOCH₃ 2-pyrimidyl 4-morpholinocarbonyl 358 SOCH₃ 2-pyrimidyl 2-methyl-1-imidazolyl 359 SOCH₃ 2-pyrimidyl 5-methyl-1-imidazolyl 360 SOCH₃ 2-pyrimidyl 2-methylsulfonyl-1-imidazolyl 361 SOCH₃ 5-pyrimidyl 2-(aminosulfonyl )phenyl 362 SOCH₃ 5-pyrimidyl 2-(methylaminosulfonyl)phenyl 363 SOCH₃ 5-pyrimidyl 1-pyrrolidinocarbonyl 364 SOCH₃ 5-pyrimidyl 2-(methylsulfonyl)phenyl 365 SOCH₃ 5-pyrimidyl 4-morpholino 366 SOCH₃ 5-pyrimidyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 367 SOCH₃ 5-pyrimidyl 4-morpholinocarbonyl 368 SOCH₃ 5-pyrimidyl 2-methyl-1-imidazolyl 369 SOCH₃ 5-pyrimidyl 5-methyl-1-imidazolyl 370 SOCH₃ 5-pyrimidyl 2-methylsulfonyl-1-imidazolyl 371 SOCH₃ 2-Cl-phenyl 2-(aminosulfonyl)phenyl 372 SOCH₃ 2-Cl-phenyl 2-(methylaminosulfonyl)phenyl 373 SOCH₃ 2-Cl-phenyl 1-pyrrolidinocarbonyl 374 SOCH₃ 2-Cl-phenyl 2-(methylsulfonyl)phenyl 375 SOCH₃ 2-Cl-phenyl 4-morpholino 376 SOCH₃ 2-Cl-phenyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 377 SOCH₃ 2-Cl-phenyl 4-morpholinocarbonyl 378 SOCH₃ 2-Cl-phenyl 2-methyl-1-imidazolyl 379 SOCH₃ 2-Cl-phenyl 5-methyl-1-imidazolyl 380 SOCH₃ 2-Cl-phenyl 2-methylsulfonyl-1-imidazolyl 381 SOCH₃ 2-F-phenyl 2-(aminosulfonyl )phenyl 382 SOCH₃ 2-F-phenyl 2-(methylaminosulfonyl)phenyl 383 SOCH₃ 2-F-phenyl 1-pyrrolidinocarbonyl 384 SOCH₃ 2-F-phenyl 2-(methylsulfonyl )phenyl 385 SOCH₃ 2-F-phenyl 4-morpholino 386 SOCH₃ 2-F-phenyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 387 SOCH₃ 2-F-phenyl 4-morpholinocarbonyl 388 SOCH₃ 2-F-phenyl 2-methyl-1-imidazolyl 389 SOCH₃ 2-F-phenyl 5-methyl-1-imidazolyl 390 SOCH₃ 2-F-phenyl 2-methylsulfonyl-1-imidazolyl 391 SOCH₃ 2,6-diF-phenyl 2-(aminosulfonyl)phenyl 392 SOCH₃ 2,6-diF-phenyl 2-(methylaminosulfonyl)phenyl 393 SOCH₃ 2,6-diF-phenyl 1-pyrrolidinocarbonyl 394 SOCH₃ 2,6-diF-phenyl 2-(methylsulfonyl)phenyl 395 SOCH₃ 2,6-diF-phenyl 4-morpholino 396 SOCH₃ 2,6-diF-phenyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 397 SOCH₃ 2,6-diF-phenyl 4-morpholinocarbonyl 398 SOCH₃ 2,6-diF-phenyl 2-methyl-1-imidazoiLyl 399 SOCH₃ 2,6-diF-phenyl 5-methyl-1-imidazolyl 400 SOCH₃ 2,6-diF-phenyl 2-methylsulfonyl-1-imidazolyl 401 SO₂CH₃ phenyl 2-(aminosulfonyl)phenyl 402 SO₂CH₃ phenyl 2-(methylaminosulfonyl)phenyl 403 SO₂CH₃ phenyl 1-pyrrolidinocarbonyl 404 SO₂CH₃ phenyl 2-(methylsulfonyl)phenyl 405 SO₂CH₃ phenyl 4-morpholino 406 SO₂CH₃ phenyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 407 SO₂CH₃ phenyl 4-morpholinocarbonyl 408 SO₂CH₃ phenyl 2-methyl-1-imidazolyl 409 SO₂CH₃ phenyl 5-methyl-1-imidazolyl 410 SO₂CH₃ phenyl 2-methylsulfonyl-1-imidazolyl 411 SO₂CH₃ 2-pyridyl 2-(amninosulfonyl)phenyl 412 SO₂CH₃ 2-pyridyl 2-(methylaminosulfonyl)phenyl 413 SO₂CH₃ 2-pyridyl 1-pyrrolidinocarbonyl 414 SO₂CH₃ 2-pyridyl 2-(methylsulfonyl)phenyl 415 SO₂CH₃ 2-pyridyl 4-morpholino 416 SO₂CH₃ 2-pyridyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 417 SO₂CH₃ 2-pyridyl 4-morpholinocarbonyl 418 SO₂CH₃ 2-pyridyl 2-methyl-1-imidazolyl 419 SO₂CH₃ 2-pyridyl 5-methyl-1-imidazolyl 420 SO₂CH₃ 2-pyridyl 2-methylsulfonyl-1-imidazolyl 421 SO₂CH₃ 3-pyridyl 2-(aminosulfonyl)phenyl 422 SO₂CH₃ 3-pyridyl 2-(methylaminosulfonyl)phenyl 423 SO₂CH₃ 3-pyridyl 1-pyrrolidinocarbonyl 424 SO₂CH₃ 3-pyridyl 2-(methylsulfonyl)phenyl 425 SO₂CH₃ 3-pyridyl 4-morpholino 426 SO₂CH₃ 3-pyridyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 427 SO₂CH₃ 3-pyridyl 4-morpholinocarbonyl 428 SO₂CH₃ 3-pyridyl 2-methyl-1-imidazolyl 429 SO₂CH₃ 3-pyridyl 5-methyl-1-imidazolyl 430 SO₂CH₃ 3-pyridyl 2-methylsulfonyl-1-imidazolyl 431 SO₂CH₃ 2-pyrimidyl 2-(aminosulfonyl)phenyl 432 SO₂CH₃ 2-pyrimidyl 2-(methylaminosulfonyl)phenyl 433 SO₂CH₃ 2-pyrimidyl 1-pyrrolidinocarbonyl 434 SO₂CH₃ 2-pyrimidyl 2-(methylsulfonyl)phenyl 435 SO₂CH₃ 2-pyrimidyl 4-morpholino 436 SO₂CH₃ 2-pyrimidyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 437 SO₂CH₃ 2-pyrimidyl 4-morpholinocarbonyl 438 SO₂CH₃ 2-pyrimidyl 2-methyl-1-imidazolyl 439 SO₂CH₃ 2-pyrimidyl 5-methyl-1-imidazolyl 440 SO₂CH₃ 2-pyrimidyl 2-methylsulfonyl-1-imidazolyl 441 SO₂CH₃ 5-pyrimidyl 2-(aminosulfonyl)phenyl 442 SO₂CH₃ 5-pyrimidyl 2-(methylaminosulfonyl)phenyl 443 SO₂CH₃ 5-pyrimidyl 1-pyrrolidinocarbonyl 444 SO₂CH₃ 5-pyrimidyl 2-(methylsulfonyl)phenyl 445 SO₂CH₃ 5-pyrimidyl 4-morpholino 446 SO₂CH₃ 5-pyrimidyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 447 SO₂CH₃ 5-pyrimidyl 4-morpholinocarbonyl 448 SO₂CH₃ 5-pyrimidyl 2-methyl-1-imidazolyl 449 SO₂CH₃ 5-pyrimidyl 5-methyl-1-imidazolyl 450 SO₂CH₃ 5-pyrimidyl 2-methylsulfonyl-1-imidazolyl 451 SO₂CH₃ 2-Cl-phenyl 2-(aminosulfonyl)phenyl 452 SO₂CH₃ 2-Cl-phenyl 2-(methylaminosulfonyl)phenyl 453 SO₂CH₃ 2-Cl-phenyl 1-pyrrolidinocarbonyl 454 SO₂CH₃ 2-Cl-phenyl 2-(methylsulfonyl)phenyl 455 SO₂CH₃ 2-Cl-phenyl 4-morpholino 456 SO₂CH₃ 2-Cl-phenyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 457 SO₂CH₃ 2-Cl-phenyl 4-morpholinocarbonyl 458 SO₂CH₃ 2-Cl-phenyl 2-methyl-1-imidazolyl 459 SO₂CH₃ 2-Cl-phenyl 5-methyl-1-imidazolyl 460 SO₂CH₃ 2-Cl-phenyl 2-methylsulfonyl-1-imidazolyl 461 SO₂CH₃ 2-F-phenyl 2-(aminosulfonyl)phenyl 462 SO₂CH₃ 2-F-phenyl 2-(methylaminosulfonyl)phenyl 463 SO₂CH₃ 2-F-phenyl 1-pyrrolidinocarbonyl 464 SO₂CH₃ 2-F-phenyl 2-(methylsulfonyl)phenyl 465 SO₂CH₃ 2-F-phenyl 4-morpholino 466 SO₂CH₃ 2-F-phenyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 467 SO₂CH₃ 2-F-phenyl 4-morpholinocarbonyl 468 SO₂CH₃ 2-F-phenyl 2-methyl-1-imidazolyl 469 SO₂CH₃ 2-F-phenyl 5-methyl-1-imidazolyl 470 SO₂CH₃ 2-F-phenyl 2-methylsulfonyl-1-imidazolyl 471 SO₂CH₃ 2,6-diF-phenyl 2-(aminosulfonyl)phenyl 472 SO₂CH₃ 2,6-diF-phenyl 2-(methylaminosulfonyl)phenyl 473 SO₂CH₃ 2,6-diF-phenyl 1-pyrrolidinocarbonyl 474 SO₂CH₃ 2,6-diF-phenyl 2-(methylsulfonyl)phenyl 475 SO₂CH₃ 2,6-diF-phenyl 4-morpholino 476 SO₂CH₃ 2,6-diF-phenyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 477 SO₂CH₃ 2,6-diF-phenyl 4-morpholinocarbonyl 478 SO₂CH₃ 2,6-diF-phenyl 2-methyl-1-imidazolyl 479 SO₂CH₃ 2,6-diF-phenyl 5-methyl-1-imidazolyl 480 SO₂CH₃ 2,6-diF-phenyl 2-methylsulfonyl-1-imidazolyl 481 CH₂NH— phenyl 2-(aminosulfonyl)phenyl SO₂CH₃ 482 CH₂NH— phenyl 2-(methylaminosulfonyl)phenyl SO₂CH₃ 483 CH₂NH— phenyl 1-pyrrolidinocarbonyl SO₂CH₃ 484 CH₂NH— phenyl 2-(methylsulfonyl)phenyl SO₂CH₃ 485 CH₂NH— phenyl 4-morpholino SO₂CH₃ 486 CH₂NH— phenyl 2-(1′-CF₃-tetrazol-2-yl)phenyl SO₂CH₃ 487 CH₂NH— phenyl 4-morpholinocarbonyl SO₂CH₃ 488 CH₂NH— phenyl 2-methyl-1-imidazolyl SO₂CH₃ 489 CH₂NH— phenyl 5-methyl-1-imidazolyl SO₂CH₃ 490 CH₂NH— phenyl 2-methylsulfonyl-1-imidazolyl SO₂CH₃ 491 CH₂NH— 2-pyridyl 2-(aminosulfonyl)phenyl SO₂CH₃ 492 CH₂NH— 2-pyridyl 2-(methylaminosulfonyl)phenyl SO₂CH₃ 493 CH₂NH— 2-pyridyl 1-pyrrolidinocarbonyl SO₂CH₃ 494 CH₂NH— 2-pyridyl 2-(methylsulfonyl)phenyl SO₂CH₃ 495 CH₂NH— 2-pyridyl 4-morpholino SO₂CH₃ 496 CH₂NH— 2-pyridyl 2-(1′-CF₃-tetrazol-2-yl)phenyl SO₂CH₃ 497 CH₂NH— 2-pyridyl 4-morpholinocarbonyl SO₂CH₃ 498 CH₂NH— 2-pyridyl 2-methyl-1-imidazolyl SO₂CH₃ 499 CH₂NH— 2-pyridyl 5-methyl-1-imidazolyl SO₂CH₃ 500 CH₂NH— 2-pyridyl 2-methylsulfonyl-1-imidazolyl SO₂CH₃ 501 CH₂NH— 3-pyridyl 2-(aminosulfonyl)phenyl SO₂CH₃ 502 CH₂NH— 3-pyridyl 2-(methylaminosulfonyl)phenyl SO₂CH₃ 503 CH₂NH— 3-pyridyl 1-pyrrolidinocarbonyl SO₂CH₃ 504 CH₂NH— 3-pyridyl 2-(methylsulfonyl)phenyl SO₂CH₃ 505 CH₂NH— 3-pyridyl 4-morpholino SO₂CH₃ 506 CH₂NH— 3-pyridyl 2-(1′-CF₃-tetrazol-2-yl)phenyl SO₂CH₃ 507 CH₂NH— 3-pyridyl 4-morpholinocarbonyl SO₂CH₃ 508 CH₂NH— 3-pyridyl 2-methyl-1-imidazolyl SO₂CH₃ 509 CH₂NH— 3-pyridyl 5-methyl-1-imidazolyl SO₂CH₃ 510 CH₂NH— 3-pyridyl 2-methylsulfonyl-1-imidazolyl SO₂CH₃ 511 CH₂NH— 2-pyrimidyl 2-(aminosulfonyl)phenyl SO₂CH₃ 512 CH₂NH— 2-pyrimidyl 2-(methylaminosulfonyl)phenyl SO₂CH₃ 513 CH₂NH— 2-pyrimidyl 1-pyrrolidinocarbonyl SO₂CH₃ 514 CH₂NH— 2-pyrimidyl 2-(methylsulfonyl)phenyl SO₂CH₃ 515 CH₂NH— 2-pyrimidyl 4-morpholino SO₂CH₃ 516 CH₂NH— 2-pyrimidyl 2-(1′-CF₃-tetrazol-2-yl)phenyl SO₂CH₃ 517 CH₂NH— 2-pyrimidyl 4-morpholinocarbonyl SO₂CH₃ 518 CH₂NH— 2-pyrimidyl 2-methyl-1-imidazolyl SO₂CH₃ 519 CH₂NH— 2-pyrimidyl 5-methyl-1-imidazolyl SO₂CH₃ 520 CH₂NH— 2-pyrimidyl 2-methylsulfonyl-1-imidazolyl SO₂CH₃ 521 CH₂NH— 5-pyrimidyl 2-(aminosulfonyl)phenyl SO₂CH₃ 522 CH₂NH— 5-pyrimidyl 2-(methylaminosulfonyl)phenyl SO₂CH₃ 523 CH₂NH— 5-pyrimidyl 1-pyrrolidinocarbonyl SO₂CH₃ 524 CH₂NH— 5-pyrimidyl 2-(methylsulfonyl)phenyl SO₂CH₃ 525 CH₂NH— 5-pyrimidyl 4-morpholino SO₂CH₃ 526 CH₂NH— 5-pyrimidyl 2-(1′-CF₃-tetrazol-2-yl)phenyl SO₂CH₃ 527 CH₂NH— 5-pyrimidyl 4-morpholinocarbonyl SO₂CH₃ 528 CH₂NH— 5-pyrimidyl 2-methyl-1-imidazolyl SO₂CH₃ 529 CH₂NH— 5-pyrimidyl 5-methyl-1-imidazolyl SO₂CH₃ 530 CH₂NH— 5-pyrimidyl 2-methylsulfonyl-1-imidazolyl SO₂CH₃ 531 CH₂NH— 2-Cl-phenyl 2-(aminosulfonyl)phenyl SO₂CH₃ 532 CH₂NH— 2-Cl-phenyl 2-(methylaminosulfonyl)phenyl SO₂CH₃ 533 CH₂NH— 2-Cl-phenyl 1-pyrrolidinocarbonyl SO₂CH₃ 534 CH₂NH— 2-Cl-phenyl 2-(methylsulfonyl)phenyl SO₂CH₃ 535 CH₂NH— 2-Cl-phenyl 4-morpholino SO₂CH₃ 536 CH₂NH— 2-Cl-phenyl 2-(1′-CF₃-tetrazol-2-yl)phenyl SO₂CH₃ 537 CH₂NH— 2-Cl-phenyl 4-morpholinocarbonyl SO₂CH₃ 538 CH₂NH— 2-Cl-phenyl 2-methyl-1-imidazolyl SO₂CH₃ 539 CH₂NH— 2-Cl-phenyl 5-methyl-1-imidazolyl SO₂CH₃ 540 CH₂NH— 2-Cl-phenyl 2-methylsulfonyl-1-imidazolyl SO₂CH₃ 541 CH₂NH— 2-F-phenyl 2-(aminosulfonyl)phenyl SO₂CH3 542 CH₂NH— 2-F-phenyl 2-(methylaminosulfonyl)phenyl SO₂CH₃ 543 CH₂NH— 2-F-phenyl 1-pyrrolidinocarbonyl SO₂CH₃ 544 CH₂NH— 2-F-phenyl 2-(methylsulfonyl)phenyl SO₂CH₃ 545 CH₂NH— 2-F-phenyl 4-morpholino SO₂CH₃ 546 CH₂NH— 2-F-phenyl 2-(1′-CF₃-tetrazol-2-yl)phenyl SO₂CH₃ 547 CH₂NH— 2-F-phenyl 4-morpholinocarbonyl SO₂CH₃ 548 CH₂NH— 2-F-phenyl 2-methyl-1-imidazolyl SO₂CH₃ 549 CH₂NH— 2-F-phenyl 5-methyl-1-imidazolyl SO₂CH₃ 550 CH₂NH— 2-F-phenyl 2-methylsulfonyl-1-imidazolyl SO₂CH₃ 551 CH₂NH— 2,6-diF-phenyl 2-(aminosulfonyl)phenyl SO₂CH₃ 552 CH₂NH— 2,6-diF-phenyl 2-(methylaminosulfonyl)phenyl SO₂CH₃ 553 CH₂NH— 2,6-diF-phenyl 1-pyrrolidinocarbonyl SO₂CH₃ 554 CH₂NH— 2,6-diF-phenyl 2-(methylsulfonyl)phenyl SO₂CH₃ 555 CH₂NH— 2,6-diF-phenyl 4-morpholino SO₂CH₃ 556 CH₂NH— 2,6-diF-phenyl 2-(1′-CF₃-tetrazol-2-yl)phenyl SO₂CH₃ 557 CH₂NH— 2,6-diF-phenyl 4-morpholinocarbonyl SO₂CH₃ 558 CH₂NH— 2,6-diF-phenyl 2-methyl-1-imidazolyl SO₂CH₃ 559 CH₂NH— 2,6-diF-phenyl 5-methyl-1-imidazolyl SO₂CH₃ 560 CH₂NH— 2,6-diF-phenyl 2-methylsulfonyl-1-imidazolyl SO₂CH₃ 561 Cl phenyl 2-(aminosulfonyl)phenyl 562 Cl phenyl 2-(methylaminosulfonyl)phenyl 563 Cl phenyl 1-pyrrolidinocarbonyl 564 Cl phenyl 2-(methylsulfonyl)phenyl 565 Cl phenyl 4-morpholino 566 Cl phenyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 567 Cl phenyl 4-morpholinocarbonyl 568 Cl phenyl 2-methyl-1-imidazolyl 569 Cl phenyl 5-methyl-1-imidazolyl 570 Cl phenyl 2-methylsulfonyl-1-imidazolyl 571 Cl 2-pyridyl 2-(aminosulfonyl)phenyl 572 Cl 2-pyridyl 2-(methylaminosulfonyl)phenyl 573 Cl 2-pyridyl 1-pyrrolidinocarbonyl 574 Cl 2-pyridyl 2-(methylsulfonyl)phenyl 575 Cl 2-pyridyl 4-morpholino 576 Cl 2-pyridyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 577 Cl 2-pyridyl 4-morpholinocarbonyl 578 Cl 2-pyridyl 2-methyl-1-imidazolyl 579 Cl 2-pyridyl 5-methyl-1-imidazolyl 580 Cl 2-pyridyl 2-methylsulfonyl-1-imidazolyl 581 Cl 3-pyridyl 2-(aminosulfonyl)phenyl 582 Cl 3-pyridyl 2-(methylaminosulfonyl )phenyl 583 Cl 3-pyridyl 1-pyrrolidinocarbonyl 584 Cl 3-pyridyl 2-(methylsulfonyl)phenyl 585 Cl 3-pyridyl 4-morpholino 586 Cl 3-pyridyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 587 Cl 3-pyridyl 4-morpholinocarbonyl 588 Cl 3-pyridyl 2-methyl-1-imidazolyl 589 Cl 3-pyridyl 5-methyl-1-imidazolyl 590 Cl 3-pyridyl 2-methylsulfonyl-1-imidazolyl 591 Cl 2-pyrimidyl 2-(aminosulfonyl)phenyl 592 Cl 2-pyrimidyl 2-(methylaminosulfonyl)phenyl 593 Cl 2-pyrimidyl 1-pyrrolidinocarbonyl 594 Cl 2-pyrimidyl 2-(methylsulfonyl)phenyl 595 Cl 2-pyrimidyl 4-morpholino 596 Cl 2-pyrimidyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 597 Cl 2-pyrimidyl 4-morpholinocarbonyl 598 Cl 2-pyrimidyl 2-methyl-1-imidazolyl 599 Cl 2-pyrimidyl 5-methyl-1-imidazolyl 600 Cl 2-pyrimidyl 2-methylsulfonyl-1-imidazolyl 601 Cl 5-pyrimidyl 2-(aminosulfonyl)phenyl 602 Cl 5-pyrimidyl 2-(methylaminosulfonyl)phenyl 603 Cl 5-pyrimidyl l-pyrrolidinocarbonyl 604 Cl 5-pyrimidyl 2-(methylsulfonyl)phenyl 605 Cl 5-pyrimidyl 4-morpholino 606 Cl 5-pyrimidyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 607 Cl 5-pyrimidyl 4-morpholinocarbonyl 608 Cl 5-pyrimidyl 2-methyl-1-imidazolyl 609 Cl 5-pyrimidyl 5-methyl-1-imidazolyl 610 Cl 5-pyrimidyl 2-methylsulfonyl-1-imidazoayl 611 Cl 2-Cl-phenyl 2-(aminosulfonyl)phenyl 612 Cl 2-Cl-phenyl 2-(methylaminosulfonyl)phenyl 613 Cl 2-Cl-phenyl 1-pyrrolidinocarbonyl 614 Cl 2-Cl-phenyl 2-(methylsulfonyl)phenyl 615 Cl 2-Cl-phenyl 4-morpholino 616 Cl 2-Cl-phenyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 617 Cl 2-Cl-phenyl 4-morpholinocarbonyl 618 Cl 2-Cl-phenyl 2-methyl-1-imidazolyl 619 Cl 2-Cl-phenyl 5-methyl-1-imidazolyl 620 Cl 2-Cl-phenyl 2-methylsulfonyl-1-imidazolyl 621 Cl 2-F-phenyl 2-(aminosulfonyl)phenyl 622 Cl 2-F-phenyl 2-(methylaminosulfonvl)phenyl 623 Cl 2-F-phenyl 1-pyrrolidinocarbonyl 624 Cl 2-F-phenyl 2-(methylsulfonyl)phenyl 625 Cl 2-F-phenyl 4-morpholino 626 Cl 2-F-phenyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 627 Cl 2-F-phenyl 4-morpholinocarbonyl 628 Cl 2-F-phenyl 2-methyl-1-imidazolyl 629 Cl 2-F-phenyl 5-methyl-1-imidazolyl 630 Cl 2-F-phenyl 2-methylsulfonyl-1-imidazolyl 631 Cl 2,6-diF-phenyl 2-(aminosulfonyl)phenyl 632 Cl 2,6-diF-phenyl 2-(methylaminosulfonyl)phenyl 633 Cl 2,6-diF-phenyl 1-pyrrolidinocarbonyl 634 Cl 2,6-diF-phenyl 2-(methylsulfonyl)phenyl 635 Cl 2,6-diF-phenyl 4-morpholino 636 Cl 2,6-diF-phenyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 637 Cl 2,6-diF-phenyl 4-morpholinocarbonyl 638 Cl 2,6-diF-phenyl 2-methyl-1-imidazolyl 639 Cl 2,6-diF-phenyl 5-methyl-1-imidazolyl 640 Cl 2,6-diF-phenyl 2-methylsulfonyl-1-imidazolyl 641 F phenyl 2-(aminosulfonyl)phenyl 642 F phenyl 2-(methylanimosulfonyl)phenyl 643 F phenyl 1-pyrrolidinocarbonyl 644 F phenyl 2-(methylsulfonyl)phenyl 645 F phenyl 4-morpholino 646 F phenyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 647 F phenyl 4-morpholinocarbonyl 648 F phenyl 2-methyl-1-imidazolyl 649 F phenyl 5-methyl-1-imidazolyl 650 F phenyl 2-methylsulfonyl-1-imidazolyl 651 F 2-pyridyl 2-(aminosulfonyl)phenyl 652 F 2-pyridyl 2-(methylaminosulfonyl)phenyl 653 F 2-pyridyl 1-pyrrolidinocarbonyl 654 F 2-pyridyl 2-(methylsulfonyl)phenyl 655 F 2-pyridyl 4-morpholino 656 F 2-pyridyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 657 F 2-pyridyl 4-morpholinocarbonyl 658 F 2-pyridyl 2-methyl-1-imidazolyl 659 F 2-pyridyl 5-methyl-1-imidazolyl 660 F 2-pyridyl 2-methylsulfonyl-1-imidazolyl 661 F 3-pyridyl 2-(aminosulfonyl)phenyl 662 F 3-pyridyl 2-(methylaminosulfonyl)phenyl 663 F 3-pyridyl 1-pyrrolidinocarbonyl 664 F 3-pyridyl 2-(methylsulfonyl)phenyl 665 F 3-pyridyl 4-morpholino 666 F 3-pyridyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 667 F 3-pyridyl 4-morpholinocarbonyl 668 F 3-pyridyl 2-methyl-1-imidazolyl 669 F 3-pyridyl 5-methyl-1-imidazolyl 670 F 3-pyridyl 2-methylsulfonyl-1-imidazolyl 671 F 2-pyrimidyl 2-(aminosulfonyl)phenyl 672 F 2-pyrimidyl 2-(methylaminosulfonyl)phenyl 673 F 2-pyrimidyl 1-pyrrolidinocarbonyl 674 F 2-pyrimidyl 2-(methylsulfonyl)phenyl 675 F 2-pyrimidyl 4-morpholino 676 F 2-pyrimidyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 677 F 2-pyrimidyl 4-morpholinocarbonyl 678 F 2-pyrimidyl 2-methyl-1-imidazolyl 679 F 2-pyrimidyl 5-methyl-1-imidazolyl 680 F 2-pyrimidyl 2-methylsulfonyl-1-imidazolyl 681 F 5-pyrimidyl 2-(aminosulfonyl)phenyl 682 F 5-pyrimidyl 2-(methylaminosulfonyl)phenyl 683 F 5-pyrimidyl 1-pyrrolidinocarbonyl 684 F 5-pyrimidyl 2-(methylsulfonyl)phenyl 685 F 5-pyrimidyl 4-morpholino 686 F 5-pyrimidyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 687 F 5-pyrimidyl 4-morpholinocarbonyl 688 F 5-pyrimidyl 2-methyl-1-imidazolyl 689 F 5-pyrimidyl 5-methyl-1-imidazolyl 690 F 5-pyrimidyl 2-methylsulfonyl-1-imidazolyl 691 F 2-Cl-phenyl 2-(aminosulfonyl)phenyl 692 F 2-Cl-phenyl 2-(methylaminosulfonyl)phenyl 693 F 2-Cl-phenyl 1-pyrrolidinocarbonyl 694 F 2-Cl-phenyl 2-(methylsulfonyl)phenyl 695 F 2-Cl-phenyl 4-morpholino 696 F 2-Cl-phenyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 697 F 2-Cl-phenyl 4-morpholinocarbonyl 698 F 2-Cl-phenyl 2-methyl-1-imidazolyl 699 F 2-Cl-phenyl 5-methyl-1-imidazolyl 700 F 2-Cl-phenyl 2-methylsulfonyl-1-imidazolyl 701 F 2-F-phenyl 2-(amninosulfonyl)phenyl 702 F 2-F-phenyl 2-(methylaminosulfonyl)phenyl 703 F 2-F-phenyl 1-pyrrolidinocarbonyl 704 F 2-F-phenyl 2-(methylsulfonyl)phenyl 705 F 2-F-phenyl 4-morpholino 706 F 2-F-phenyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 707 F 2-F-phenyl 4-morpholinocarbonyl 708 F 2-F-phenyl 2-methyl-1-imidazolyl 709 F 2-F-phenyl 5-methyl-1-imidazolyl 710 F 2-F-phenyl 2-methylsulfonyl-1-imidazolyl 711 F 2,6-diF-phenyl 2-(aminosulfonyl)phenyl 712 F 2,6-diF-phenyl 2-(methylaminosulfonyl)phenyl 713 F 2,6-diF-phenyl 1-pyrrolidinocarbonyl 714 F 2,6-diF-phenyl 2-(methylsulfonyl)phenyl 715 F 2,6-diF-phenyl 4-morpholino 716 F 2,6-diF-phenyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 717 F 2,6-diF-phenyl 4-morpholinocarbonyl 718 F 2,6-diF-phenyl 2-methyl-1-imidazolyl 719 F 2,6-diF-phenyl 5-methyl-1-imidazolyl 720 F 2,6-diF-phenyl 2-methylsulfonyl-1-imidazolyl 721 CO₂CH₃ phenyl 2-(aminosulfonyl)phenyl 722 CO₂CH₃ phenyl 2-(methylaminosulfonyl)phenyl 723 CO₂CH₃ phenyl 1-pyrrolidinocarbonyl 724 CO₂CH₃ phenyl 2-(methylsulfonyl )phenyl 725 CO₂CH₃ phenyl 4-morpholino 726 CO₂CH₃ phenyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 727 CO₂CH₃ phenyl 4-morpholinocarbonyl 728 CO₂CH₃ phenyl 2-methyl-1-imidazolyl 729 CO₂CH₃ phenyl 5-methyl-1-imidazolyl 730 CO₂CH₃ phenyl 2-methylsulfonyl-1-imidazolyl 731 CO₂CH₃ 2-pyridyl 2-(aminosulfonyl)phenyl 732 CO₂CH₃ 2-pyridyl 2-(methylaminosulfonyl)phenyl 733 CO₂CH₃ 2-pyridyl 1-pyrrolidinocarbonyl 734 CO₂CH₃ 2-pyridyl 2-(methylsulfonyl)phenyl 735 CO₂CH₃ 2-pyridyl 4-morpholino 736 CO₂CH₃ 2-pyridyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 737 CO₂CH₃ 2-pyridyl 4-morpholinocarbonyl 738 CO₂CH₃ 2-pyridyl 2-methyl-1-imidazolyl 739 CO₂CH₃ 2-pyridyl 5-methyl-1-imidazolyl 740 CO₂CH₃ 2-pyridyl 2-methylsulfonyl-1-imidazolyl 741 CO₂CH₃ 3-pyridyl 2-(aminosulfonyl)phenyl 742 CO₂CH₃ 3-pyridyl 2-(methylaminosulfonyl)phenyl 743 CO₂CH₃ 3-pyridyl 1-pyrrolidinocarbonyl 744 CO₂CH₃ 3-pyridyl 2-(methylsulfonyl)phenyl 745 CO₂CH₃ 3-pyridyl 4-morpholino 746 CO₂CH₃ 3-pyridyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 747 CO₂CH₃ 3-pyridyl 4-morpholinocarbonyl 748 CO₂CH₃ 3-pyridyl 2-methyl-1-imidazolyl 749 CO₂CH₃ 3-pyridyl 5-methyl-1-imidazolyl 750 CO₂CH₃ 3-pyridyl 2-methylsulfonyl-1-imidazolyl 751 CO₂CH₃ 2-pyrimidyl 2-(aminosulfonyl)phenyl 752 CO₂CH₃ 2-pyrimidyl 2-(methylaminosulfonyl)phenyl 753 CO₂CH₃ 2-pyrimidyl 1-pyrrolidinocarbonyl 754 CO₂CH₃ 2-pyrimidyl 2-(methylsulfonyl)phenyl 755 CO₂CH₃ 2-pyrimidyl 4-morpholino 756 CO₂CH₃ 2-pyrimidyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 757 CO₂CH₃ 2-pyrimidyl 4-morpholinocarbonyl 758 CO₂CH₃ 2-pyrimidyl 2-methyl-1-imidazolyl 759 CO₂CH₃ 2-pyrimidyl 5-methyl-1-imidazolyl 760 CO₂CH₃ 2-pyrimidyl 2-methylsulfonyl-1-imidazolyl 761 CO₂CH₃ 5-pyrimidyl 2-(aminosulfonyl)phenyl 762 CO₂CH₃ 5-pyrimidyl 2-(methylaminosulfonyl)phenyl 763 CO₂CH₃ 5-pyrimidyl 1-pyrrolidinocarbonyl 764 CO₂CH₃ 5-pyrimidyl 2-(methylsulfonyl )phenyl 765 CO₂CH₃ 5-pyrimidyl 4-morpholino 766 CO₂CH₃ 5-pyrimidyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 767 CO₂CH₃ 5-pyrimidyl 4-morpholinocarbonyl 768 CO₂CH₃ 5-pyrimidyl 2-methyl-1-imidazolyl 769 CO₂CH₃ 5-pyrimidyl 5-methyl-1-imidazolyl 770 CO₂CH₃ 5-pyrimidyl 2-methylsulfonyl-1-imidazolyl 771 CO₂CH₃ 2-Cl-phenyl 2-(aminosulfonyl)phenyl 772 CO₂CH₃ 2-Cl-phenyl 2-(methylaminosulfonyl)phenyl 773 CO₂CH₃ 2-Cl-phenyl 1-pyrrolidinocarbonyl 774 CO₂CH₃ 2-Cl-phenyl 2-(methylsulfonyl)phenyl 775 CO₂CH₃ 2-Cl-phenyl 4-morpholino 776 CO₂CH₃ 2-Cl-phenyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 777 CO₂CH₃ 2-Cl-phenyl 4-morpholinocarbonyl 778 CO₂CH₃ 2-Cl-phenyl 2-methyl-1-imidazolyl 779 CO₂CH₃ 2-Cl-phenyl 5-methyl-1-imidazolyl 780 CO₂CH₃ 2-Cl-phenyl 2-methylsulfonyl-1-imidazolyl 781 CO₂CH₃ 2-F-phenyl 2-(aminosulfonyl)phenyl 782 CO₂CH₃ 2-F-phenyl 2-(methylaminosulfonyl)phenyl 783 CO₂CH₃ 2-F-phenyl 1-pyrrolidinocarbonyl 784 CO₂CH₃ 2-F-phenyl 2-(methylsulfonyl)phenyl 785 CO₂CH₃ 2-F-phenyl 4-ruorpholino 786 CO₂CH₃ 2-F-phenyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 787 CO₂CH₃ 2-F-phenyl 4-morpholinocarbonyl 788 CO₂CH₃ 2-F-phenyl 2-methyl-1-imidazolyl 789 CO₂CH₃ 2-F-phenyl 5-methyl-1-imidazolyl 790 CO₂CH₃ 2-F-phenyl 2-methylsulfonyl-1-imidazolyl 791 CO₂CH₃ 2,6-diF-phenyl 2-(aminosulfonyl)phenyl 792 CO₂CH₃ 2,6-diF-phenyl 2-(methylaminosulfonyl)phenyl 793 CO₂CH₃ 2,6-diF-phenyl 1-pyrrolidinocarbonyl 794 CO₂CH₃ 2,6-diF-phenyl 2-(methylsulfonyl)phenyl 795 CO₂CH₃ 2,6-diF-phenyl 4-morpholino 796 CO₂CH₃ 2,6-diF-phenyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 797 CO₂CH₃ 2,6-diF-phenyl 4-morpholinocarbonyl 798 CO₂CH₃ 2,6-diF-phenyl 2-methyl-1-imidazolyl 799 CO₂CH₃ 2,6-diF-phenyl 5-methyl-1-imidazolyl 800 CO₂CH₃ 2,6-diF-phenyl 2-methylsulfonyl-1-imidazolyl 801 CH₂OCH₃ phenyl 2-(aminosulfonyl)phenyl 802 CH₂OCH₃ phenyl 2-(methylaminosulfonyl)phenyl 803 CH₂OCH₃ phenyl 1-pyrrolidinocarbonyl 804 CH₂OCH₃ phenyl 2-(methylsulfonyl)phenyl 805 CH₂OCH₃ phenyl 4-morpholino 806 CH₂OCH₃ phenyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 807 CH₂OCH₃ phenyl 4-morpholinocarbonyl 808 CH₂OCH₃ phenyl 2-methyl-1-imidazolyl 809 CH₂OCH₃ phenyl 5-methyl-1-imidazolyl 810 CH₂OCH₃ phenyl 2-methylsulfonyl-1-imidazolyl 811 CH₂OCH₃ 2-pyridyl 2-(aminosulfonyl)phenyl 812 CH₂OCH₃ 2-pyridyl 2-(methylaminosulfonyl)phenyl 813 CH₂OCH₃ 2-pyridyl 1-pyrrolidinocarbonyl 814 CH₂OCH₃ 2-pyridyl 2-(methylsulfonyl)phenyl 815 CH₂OCH₃ 2-pyridyl 4-morpholino 816 CH₂OCH₃ 2-pyridyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 817 CH₂OCH₃ 2-pyridyl 4-morpholinocarbonyl 818 CH₂OCH₃ 2-pyridyl 2-methyl-1-imidazolyl 819 CH₂OCH₃ 2-pyridyl 5-methyl-1-imidazolyl 820 CH₂OCH₃ 2-pyridyl 2-methylsulfonyl-1-imidazolyl 821 CH₂OCH₃ 3-pyridyl 2-(aminosulfonyl)phenyl 822 CH₂OCH₃ 3-pyridyl 2-(methylaminosulfonyl)phenyl 823 CH₂OCH₃ 3-pyridyl 1-pyrrolidinocarbonyl 824 CH₂OCH₃ 3-pyridyl 2-(methylsulfonyl)phenyl 825 CH₂OCH₃ 3-pyridyl 4-morpholino 826 CH₂OCH₃ 3-pyridyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 827 CH₂OCH₃ 3-pyridyl 4-morpholinocarbonyl 828 CH₂OCH₃ 3-pyridyl 2-methyl-1-imidazolyl 829 CH₂OCH₃ 3-pyridyl 5-methyl-1-imidazolyl 830 CH₂OCH₃ 3-pyridyl 2-methylsulfonyl-1-imidazolyl 831 CH₂OCH₃ 2-pyrimidyl 2-(aminosulfonyl)phenyl 832 CH₂OCH₃ 2-pyrimidyl 2-(methylaminosulfonyl)phenyl 833 CH₂OCH₃ 2-pyrimidyl 1-pyrrolidinocarbonyl 834 CH₂OCH₃ 2-pyrimidyl 2-(methylsulfonyl)phenyl 835 CH₂OCH₃ 2-pyrimidyl 4-morpholino 836 CH₂OCH₃ 2-pyrimidyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 837 CH₂OCH₃ 2-pyrimidyl 4-morpholinocarbonyl 838 CH₂OCH₃ 2-pyrimidyl 2-methyl-1-imidazolyl 839 CH₂OCH₃ 2-pyrimidyl 5-methyl-1-imidazolyl 840 CH₂OCH₃ 2-pyrimidyl 2-methylsulfonyl-1-imidazolyl 841 CH₂OCH₃ 5-pyrimidyl 2-(aminosulfonyl)phenyl 842 CH₂OCH₃ 5-pyrimidyl 2-(methylaminosulfonyl)phenyl 843 CH₂OCH₃ 5-pyrimidyl 1-pyrrolidinocarbonyl 844 CH₂OCH₃ 5-pyrimidyl 2-(methylsulfonyl)phenyl 845 CH₂OCH₃ 5-pyrimidyl 4-morpholino 846 CH₂OCH₃ 5-pyrimidyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 847 CH₂OCH₃ 5-pyrimidyl 4-morpholinocarbonyl 848 CH₂OCH₃ 5-pyrimidyl 2-methyl-1-imidazolyl 849 CH₂OCH₃ 5-pyrimidyl 5-methyl-1-imidazolyl 850 CH₂OCH₃ 5-pyrimidyl 2-methylsulfonyl-1-imidazolyl 851 CH₂OCH₃ 2-Cl-phenyl 2-(aminosulfonyl)phenyl 852 CH₂OCH₃ 2-Cl-phenyl 2-(methylaminosulfonyl)phenyl 853 CH₂OCH₃ 2-Cl-phenyl 1-pyrrolidinocarbonyl 854 CH₂OCH₃ 2-Cl-phenyl 2-(methylsulfonyl)phenyl 855 CH₂OCH₃ 2-Cl-phenyl 4-morpholino 856 CH₂OCH₃ 2-Cl-phenyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 857 CH₂OCH₃ 2-Cl-phenyl 4-morpholinocarbonyl 858 CH₂OCH₃ 2-Cl-phenyl 2-methyl-1-imidazolyl 859 CH₂OCH₃ 2-Cl-phenyl 5-methyl-1-imidazolyl 860 CH₂OCH₃ 2-Cl-phenyl 2-methylsulfonyl-1-imidazolyl 861 CH₂OCH₃ 2-F-phenyl 2-(aminosulfonyl)phenyl 862 CH₂OCH₃ 2-F-phenyl 2-(methylaminosulfonyl)phenyl 863 CH₂OCH₃ 2-F-phenyl 1-pyrrolidinocarbonyl 864 CH₂OCH₃ 2-F-phenyl 2-(methylsulfonyl)phenyl 865 CH₂OCH₃ 2-F-phenyl 4-morpholino 866 CH₂OCH₃ 2-F-phenyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 867 CH₂OCH₃ 2-F-phenyl 4-morpholinocarbonyl 868 CH₂OCH₃ 2-F-phenyl 2-methyl-1-imidazolyl 869 CH₂OCH₃ 2-F-phenyl 5-methyl-1-imidazolyl 870 CH₂OCH₃ 2-F-phenyl 2-methylsulfonyl-1-imidazolyl 871 CH₂OCH₃ 2,6-diF-phenyl 2-(aminosulfonyl)phenyl 872 CH₂OCH₃ 2,6-diF-phenyl 2-(methylaminosulfonyl)phenyl 873 CH₂OCH₃ 2,6-diF-phenyl 1-pyrrolidinocarbonyl 874 CH₂OCH₃ 2,6-diF-phenyl 2-(methylsulfonyl)phenyl 875 CH₂OCH₃ 2,6-diF-phenyl 4-morpholino 876 CH₂OCH₃ 2,6-diF-phenyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 877 CH₂OCH₃ 2,6-diF-phenyl 4-morpholinocarbonyl 878 CH₂OCH₃ 2,6-diF-phenyl 2-methyl-1-imidazolyl 879 CH₂OCH₃ 2,6-diF-phenyl 5-methyl-1-imidazolyl 880 CH₂OCH₃ 2,6-diF-phenyl 2-methylsulfonyl-1-imidazolyl 881 CONH₂ phenyl 2-(aminosulfonyl)phenyl 882 CONH₂ phenyl 2-(methylaminosulfonyl)phenyl 883 CONH₂ phenyl 1-pyrrolidinocarbonyl 884 CONH₂ phenyl 2-(methylsulfonyl)phenyl 885 CONH₂ phenyl 4-morpholino 886 CONH₂ phenyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 887 CONH₂ phenyl 4-morpholinocarbonyl 888 CONH₂ phenyl 2-methyl-1-imidazolyl 889 CONH₂ phenyl 5-methyl-1-imidazolyl 890 CONH₂ phenyl 2-methylsulfonyl-1-imidazolyl 891 CONH₂ 2-pyridyl 2-(aminosulfonyl)phenyl 892 CONH₂ 2-pyridyl 2-(methylaminosulfonyl)phenyl 893 CONH₂ 2-pyridyl 1-pyrrolidinocarbonyl 894 CONH₂ 2-pyridyl 2-(methylsulfonyl)phenyl 895 CONH₂ 2-pyridyl 4-morpholino 896 CONH₂ 2-pyridyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 897 CONH₂ 2-pyridyl 4-morpholinocarbonyl 898 CONH₂ 2-pyridyl 2-methyl-1-imidazolyl 899 CONH₂ 2-pyridyl 5-methyl-1-imidazolyl 900 CONH₂ 2-pyridyl 2-methylsulfonyl-1-imidazolyl 901 CONH₂ 3-pyridyl 2-(aminosulfonyl)phenyl 902 CONH₂ 3-pyridyl 2-(methylaminosulfonyl)phenyl 903 CONH₂ 3-pyridyl 1-pyrrolidinocarbonyl 904 CONH₂ 3-pyridyl 2-(methylsulfonyl)phenyl 905 CONH₂ 3-pyridyl 4-morpholino 906 CONH₂ 3-pyridyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 907 CONH₂ 3-pyridyl 4-morpholinocarbonyl 908 CONH₂ 3-pyridyl 2-methyl-1-imidazolyl 909 CONH₂ 3-pyridyl 5-methyl-1-imidazolyl 910 CONH₂ 3-pyridyl 2-methylsulfonyl-1-imidazolyl 911 CONH₂ 2-pyrimidyl 2-(aminosulfonyl)phenyl 912 CONH₂ 2-pyrimidyl 2-(methylaminosulfonyl)phenyl 913 CONH₂ 2-pyrimidyl 1-pyrrolidinocarbonyl 914 CONH₂ 2-pyrimidyl 2-(methylsulfonyl)phenyl 915 CONH₂ 2-pyrimidyl 4-morpholino 916 CONH₂ 2-pyrimidyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 917 CONH₂ 2-pyrimidyl 4-morpholinocarbonyl 918 CONH₂ 2-pyrimidyl 2-methyl-1-imidazolyl 919 CONH₂ 2-pyrimidyl 5-methyl-1-imidazolyl 920 CONH₂ 2-pyrimidyl 2-methylsulfonyl-1-imidazolyl 921 CONH₂ 5-pyrimidyl 2-(aminosulfonyl)phenyl 922 CONH₂ 5-pyrimidyl 2-(methylaminosulfonyl)phenyl 923 CONH₂ 5-pyrimidyl 1-pyrrolidinocarbonyl 924 CONH₂ 5-pyrimidyl 2-(methylsulfonyl)phenyl 925 CONH₂ 5-pyrimidyl 4-morpholino 926 CONH₂ 5-pyrimidyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 927 CONH₂ 5-pyrimidyl 4-morpholinocarbonyl 928 CONH₂ 5-pyrimidyl 2-methyl-1-imidazolyl 929 CONH₂ 5-pyrimidyl 5-methyl-1-imidazolyl 930 CONH₂ 5-pyrimidyl 2-methylsulfonyl-1-imidazolyl 931 CONH₂ 2-Cl-phenyl 2-(aminosulfonyl)phenyl 932 CONH₂ 2-Cl-phenyl 2-(methylamninosulfonyl)phenyl 933 CONH₂ 2-Cl-phenyl 1-pyrrolidinocarbonyl 934 CONH₂ 2-Cl-phenyl 2-(methylsulfonyl)phenyl 935 CONH₂ 2-Cl-phenyl 4-morpholino 936 CONH₂ 2-Cl-phenyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 937 CONH₂ 2-Cl-phenyl 4-morpholinocarbonyl 938 CONH₂ 2-Cl-phenyl 2-methyl-1-imidazolyl 939 CONH₂ 2-Cl-phenyl 5-methyl-1-imidazolyl 940 CONH₂ 2-Cl-phenyl 2-methylsulfonyl-1-imidazolyl 941 CONH₂ 2-F-phenyl 2-(aminosulfonyl)phenyl 942 CONH₂ 2-F-phenyl 2-(methylaminosulfonyl)phenyl 943 CONH₂ 2-F-phenyl 1-pyrrolidinocarbonyl 944 CONH₂ 2-F-phenyl 2-(methylsulfonyl)phenyl 945 CONH₂ 2-F-phenyl 4-morpholino 946 CONH₂ 2-F-phenyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 947 CONH₂ 2-F-phenyl 4-morpholinocarbonyl 948 CONH₂ 2-F-phenyl 2-methyl-1-imidazolyl 949 CONH₂ 2-F-phenyl 5-methyl-1-imidazolyl 950 CONH₂ 2-F-phenyl 2-methylsulfonyl-1-imidazolyl 951 CONH₂ 2,6-diF-phenyl 2-(aminosulfonyl)phenyl 952 CONH₂ 2,6-diF-phenyl 2-(methylaminosulfonyl)phenyl 953 CONH₂ 2,6-diF-phenyl 1-pyrrolidinocarbonyl 954 CONH₂ 2,6-diF-phenyl 2-(methylsulfonyl)phenyl 955 CONH₂ 2,6-diF-phenyl 4-morpholino 956 CONH₂ 2,6-diF-phenyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 957 CONH₂ 2,6-diF-phenyl 4-morpholinocarbonyl 958 CONH₂ 2,6-diF-phenyl 2-methyl-1-imidazolyl 959 CONH₂ 2,6-diF-phenyl 5-methyl-1-imidazolyl 960 CONH₂ 2,6-diF-phenyl 2-methylsulfonyl-1-imidazolyl

[0246] TABLE 2

Ex # A B  1 phenyl 2-(aminosulfonyl)phenyl  2 phenyl 2-(methylaminosulfonyl)phenyl  3 phenyl 1-pyrrolidinocarbonyl  4 phenyl 2-(methylsulfonyl)phenyl  5 phenyl 4-morpholino  6 phenyl 2-(1′-CF₃-tetrazol-2-yl)phenyl  7 phenyl 4-morpholinocarbonyl  8 phenyl 2-methyl-1-imidazolyl  9 phenyl 5-methyl-1-imidazolyl 10 phenyl 2-methylsulfonyl-1-imidazolyl 11 2-pyridyl 2-(aminosulfonyl)phenyl 12 2-pyridyl 2-(methylaminosulfonyl)phenyl 13 2-pyridyl 1-pyrrolidinocarbonyl 14 2-pyridyl 2-(methylsulfonyl)phenyl 15 2-pyridyl 4-morpholino 16 2-pyridyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 17 2-pyridyl 4-morpholinocarbonyl 18 2-pyridyl 2-methyl-1-imidazolyl 19 2-pyridyl 5-methyl-1-imidazolyl 20 2-pyridyl 2-methylsulfonyl-1-imidazolyl 21 3-pyridyl 2-(aminosulfonyl)phenyl 22 3-pyridyl 2-(methylaminosulfonyl)phenyl 23 3-pyridyl 1-pyrrolidinocarbonyl 24 3-pyridyl 2-(methylsulfonyl)phenyl 25 3-pyridyl 4-morpholino 26 3-pyridyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 27 3-pyridyl 4-morpholinocarbonyl 28 3-pyridyl 2-methyl-1-imidazolyl 29 3-pyridyl 5-methyl-1-imidazolyl 30 3-pyridyl 2-methylsulfonyl-1-imidazolyl 31 2-pyrimidyl 2-(aminosulfonyl)phenyl 32 2-pyrimidyl 2-(methylaminosulfonyl)phenyl 33 2-pyrimidyl 1-pyrrolidinocarbonyl 34 2-pyrimidyl 2-(methylsulfonyl)phenyl 35 2-pyrimidyl 4-morpholino 36 2-pyrimidyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 37 2-pyrimidyl 4-morpholinocarbonyl 38 2-pyrimidyl 2-methyl-1-imidazolyl 39 2-pyrimidyl 5-methyl-1-imidazolyl 40 2-pyrimidyl 2-methylsulfonyl-1-imidazolyl 41 5-pyrimidyl 2-(aminosulfonyl)phenyl 42 5-pyrimidyl 2-(methylaminosulfonyl)phenyl 43 5-pyrimidyl 1-pyrrolidinocarbonyl 44 5-pyrimidyl 2-(methylsulfonyl)phenyl 45 5-pyrimidyl 4-morpholino 46 5-pyrimidyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 47 5-pyrimidyl 4-morpholinocarbonyl 48 5-pyrimidyl 2-methyl-1-imidazolyl 49 5-pyrimidyl 5-methyl-1-imidazolyl 50 5-pyrimidyl 2-methylsulfonyl-1-imidazolyl 51 2-Cl-phenyl 2-(aminosulfonyl)phenyl 52 2-Cl-phenyl 2-(methylaminosulfonyl)phenyl 53 2-Cl-phenyl 1-pyrrolidinocarbonyl 54 2-Cl-phenyl 2-(methylsulfonyl)phenyl 55 2-Cl-phenyl 4-morpholino 56 2-Cl-phenyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 57 2-Cl-phenyl 4-morpholinocarbonyl 58 2-Cl-phenyl 2-methyl-1-imidazolyl 59 2-Cl-phenyl 5-methyl-1-imidazolyl 60 2-Cl-phenyl 2-methylsulfonyl-1-imidazolyl 61 2-F-phenyl 2-(aminosulfonyl)phenyl 62 2-F-phenyl 2-(methylaminosulfonyl)phenyl 63 2-F-phenyl 1-pyrrolidinocarbonyl 64 2-F-phenyl 2-(methylsulfonyl)phenyl 65 2-F-phenyl 4-morpholino 66 2-F-phenyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 67 2-F-phenyl 4-morpholinocarbonyl 68 2-F-phenyl 2-methyl-1-imidazolyl 69 2-F-phenyl 5-methyl-1-imidazolyl 70 2-F-phenyl 2-methylsulfonyl-1-imidazolyl 71 2,6-diF-phenyl 2-(aminosulfonyl)phenyl 72 2,6-diF-phenyl 2-(methylaminosulfonyl)phenyl 73 2,6-diF-phenyl 1-pyrrolidinocarbonyl 74 2,6-diF-phenyl 2-(methylsulfonyl)phenyl 75 2,6-diF-phenyl 4-morpholino 76 2,6-diF-phenyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 77 2,6-diF-phenyl 4-morpholinocarbonyl 78 2,6-diF-phenyl 2-methyl-1-imidazolyl 79 2,6-diF-phenyl 5-methyl-1-imidazolyl 80 2,6-diF-phenyl 2-methylsulfonyl-imidazolyl

Utility

[0247] The compounds of this invention are useful as anticoagulants for the treatment or prevention of thromboembolic disorders in mammals. The term “thromboembolic disorders” as used herein includes arterial or venous cardiovascular or cerebrovascular thromboembolic disorders, including, for example, unstable angina, first or recurrent myocardial infarction, ischemic sudden death, transient ischemic attack, stroke, atherosclerosis, venous thrombosis, deep vein thrombosis, thrombophlebitis, arterial embolism, coronary and cerebral arterial thrombosis, cerebral embolism, kidney embolisms, and pulmonary embolisms. The anticoagulant effect of compounds of the present invention is believed to be due to inhibition of factor Xa or thrombin.

[0248] The effectiveness of compounds of the present invention as inhibitors of factor Xa was determined using purified human factor Xa and synthetic substrate. The rate of factor Xa hydrolysis of chromogenic substrate S2222 (Kabi Pharmacia, Franklin, Ohio) was measured both in the absence and presence of -compounds of the present invention. Hydrolysis of the substrate resulted in the release of pNA, which was monitored spectrophotometrically by measuring the increase in absorbance at 405 nM. A decrease in the rate of absorbance change at 405 nm in the presence of inhibitor is indicative of enzyme inhibition. The results of this assay are expressed as inhibitory constant, K_(i).

[0249] Factor Xa determinations were made in 0.10 M sodium phosphate buffer, pH 7.5, containing 0.20 M NaCl, and 0.5% PEG 8000. The Michaelis constant, K_(m), for substrate hydrolysis was determined at 25° C. using the method of Lineweaver and Burk. Values of K_(i) were determined by allowing 0.2-0.5 nM human factor Xa (Enzyme Research Laboratories, South Bend, Ind.) to react with the substrate (0.20 mM-1 mM) in the presence of inhibitor. Reactions were allowed to go for 30 minutes and the velocities (rate of absorbance change vs time) were measured in the time frame of 25-30 minutes. The following relationship was used to calculate K_(i) values:

(v_(o)−v_(s))/v_(s)=I/(K_(i)(1+S/K_(m)))

[0250] where:

[0251] v_(o) is the velocity of the control in the absence of inhibitor;

[0252] v_(s) is the velocity in the presence of inhibitor;

[0253] I is the concentration of inhibitor;

[0254] K_(i) is the dissociation constant of the enzyme:inhibitor complex;

[0255] S is the concentration of substrate;

[0256] K_(m) is the Michaelis constant.

[0257] Using the methodology described above, a compound of the present invention were found to exhibit a K_(i) of ≦10 μM, thereby confirming the utility of the compounds of the present invention as effective Xa inhibitors.

[0258] The antithrombotic effect of compounds of the present invention can be demonstrated in a rabbit arterio-venous (AV) shunt thrombosis model. In this model, rabbits weighing 2-3 kg anesthetized with a mixture of xylazine (10 mg/kg i.m.) and ketamine (50 mg/kg i.m.) are used. A saline-filled AV shunt device is connected between the femoral arterial and the femoral venous cannulae. The AV shunt device consists of a piece of 6-cm tygon tubing which contains a piece of silk thread. Blood will flow from the femoral artery via the AV-shunt into the femoral vein. The exposure of flowing blood to a silk thread will induce the formation of a significant thrombus. After forty minutes, the shunt is disconnected and the silk thread covered with thrombus is weighed. Test agents or vehicle will be given (i.v., i.p., s.c., or orally) prior to the opening of the AV shunt. The percentage inhibition of thrombus formation is determined for each treatment group. The ID50 values (dose which produces 50% inhibition of thrombus formation) are estimated by linear regression.

[0259] The compounds of formula (I) may also be useful as inhibitors of serine proteases, notably human thrombin, plasma kallikrein and plasmin. Because of their inhibitory action, these compounds are indicated for use in the prevention or treatment of physiological reactions, blood coagulation and inflammation, catalyzed by the aforesaid class of enzymes. Specifically, the compounds have utility as drugs for the treatment of diseases arising from elevated thrombin activity such as myocardial infarction, and as reagents used as anticoagulants in the processing of blood to plasma for diagnostic and other commercial purposes.

[0260] Some compounds of the present invention were shown to be direct acting inhibitors of the serine protease thrombin by their ability to inhibit the cleavage of small molecule substrates by thrombin in a purified system. In vitro inhibition constants were determined by the method described by Kettner et al. in J. Biol. Chem. 265, 18289-18297 (1990), herein incorporated by reference. In these assays, thrombin-mediated hydrolysis of the chromogenic substrate S2238 (Helena Laboratories, Beaumont, Tex.) was monitored spectrophotometrically. Addition of an inhibitor to the assay mixture results in decreased absorbance and is indicative of thrombin inhibition. Human thrombin (Enzyme Research Laboratories, Inc., South Bend, Ind.) at a concentration of 0.2 nM in 0.10 M sodium phosphate buffer, pH 7.5, 0.20 M NaCl, and 0.5% PEG 6000, was incubated with various substrate concentrations ranging from 0.20 to 0.02 mM. After 25 to 30 minutes of incubation, thrombin activity was assayed by monitoring the rate of increase in absorbance at 405 nm which arises owing to substrate hydrolysis. Inhibition constants were derived from reciprocal plots of the reaction velocity as a function of substrate concentration using the standard method of Lineweaver and Burk. Using the methodology described above, some compounds of this invention were evaluated and found to exhibit a K_(i) of less than 10 μm, thereby confirming the utility of the compounds of the present invention as effective thrombin inhibitors.

[0261] The compounds of the present invention can be administered alone or in combination with one or more additional therapeutic agents. These include other anti-coagulant or coagulation inhibitory agents, anti-platelet or platelet inhibitory agents, thrombin inhibitors, or thrombolytic or fibrinolytic agents.

[0262] The compounds are administered to a mammal in a therapeutically effective amount. By “therapeutically effective amount” it is meant an amount of a compound of Formula I that, when administered alone or in combination with an additional therapeutic agent to a mammal, is effective to prevent or ameliorate the thromboembolic disease condition or the progression of the disease.

[0263] By “administered in combination” or “combination therapy” it is meant that the compound of Formula I and one or more additional therapeutic agents are administered concurrently to the mammal being treated. When administered in combination each component may be administered at the same time or sequentially in any order at different points in time. Thus, each component may be administered separately but sufficiently closely in time so as to provide the desired therapeutic effect. Other anticoagulant agents (or coagulation inhibitory agents) that may be used in combination with the compounds of this invention include warfarin and heparin, as well as other factor Xa inhibitors such as those described in the publications identified above under Background of the Invention.

[0264] The term anti-platelet agents (or platelet inhibitory agents), as used herein, denotes agents that inhibit platelet function such as by inhibiting the aggregation, adhesion or granular secretion of platelets. Such agents include, but are not limited to, the various known non-steroidal anti-inflammatory drugs (NSAIDS) such as aspirin, ibuprofen, naproxen, sulindac, indomethacin, mefenamate, droxicam, diclofenac, sulfinpyrazone, and piroxicam, including pharmaceutically acceptable salts or prodrugs thereof. Of the NSAIDS, aspirin (acetylsalicyclic acid or ASA), and piroxicam are preferred. Other suitable anti-platelet agents include ticlopidine, including pharmaceutically acceptable salts or prodrugs thereof. Ticlopidine is also a preferred compound since it is known to be gentle on the gastro-intestinal tract in use. Still other suitable platelet inhibitory agents include IIb/IIIa antagonists, thromboxane-A2-receptor antagonists and thromboxane-A2-synthetase inhibitors, as well as pharmaceutically acceptable salts or prodrugs thereof.

[0265] The term thrombin inhibitors (or anti-thrombin agents), as used herein, denotes inhibitors of the serine protease thrombin. By inhibiting thrombin, various thrombin-mediated processes, such as thrombin-mediated platelet activation (that is, for example, the aggregation of platelets, and/or the granular secretion of plasminogen activator inhibitor-1 and/or serotonin) and/or fibrin formation are disrupted. A number of thrombin inhibitors are known to one of skill in the art and these inhibitors are contemplated to be used in combination with the present compounds. Such inhibitors include, but are not limited to, boroarginine derivatives, boropeptides, heparins, hirudin and argatroban, including pharmaceutically acceptable salts and prodrugs thereof. Boroarginine derivatives and boropeptides include N-acetyl and peptide derivatives of boronic acid, such as C-terminal a-aminoboronic acid derivatives of lysine, ornithine, arginine, homoarginine and corresponding isothiouronium analogs thereof. The term hirudin, as used herein, includes suitable derivatives or analogs of hirudin, referred to herein as hirulogs, such as disulfatohirudin. Boropeptide thrombin inhibitors include compounds described in Kettner et al., U.S. Pat. No. 5,187,157 and European Patent Application Publication Number 293 881 A2, the disclosures of which are hereby incorporated herein by reference. Other suitable boroarginine derivatives and boropeptide thrombin inhibitors include those disclosed in PCT Application Publication Number 92/07869 and European Patent Application Publication Number 471,651 A2, the disclosures of which are hereby incorporated herein by reference.

[0266] The term thrombolytics (or fibrinolytic) agents (or thrombolytics or fibrinolytics), as used herein, denotes agents that lyse blood clots (thrombi). Such agents include tissue plasminogen activator, anistreplase, urokinase or streptokinase, including pharmaceutically acceptable salts or prodrugs thereof. The term anistreplase, as used herein, refers to anisoylated plasminogen streptokinase activator complex, as described, for example, in European Patent Application No. 028,489, the disclosure of which is hereby incorporated herein by reference herein. The term urokinase, as used herein, is intended to denote both dual and single chain urokinase, the latter also being referred to herein as prourokinase.

[0267] Administration of the compounds of Formula I of the invention in combination with such additional therapeutic agent, may afford an efficacy advantage over the compounds and agents alone, and may do so while permitting the use of lower doses of each. A lower dosage minimizes the potential of side effects, thereby providing an increased margin of safety.

[0268] The compounds of the present invention are also useful as standard or reference compounds, for example as a quality standard or control, in tests or assays involving the inhibition of factor Xa. Such compounds may be provided in a commercial kit, for example, for use in pharmaceutical research involving factor Xa. For example, a compound of the present invention could be used as a reference in an assay to compare its known activity to a compound with an unknown activity. This would ensure the experimenter that the assay was being performed properly and provide a basis for comparison, especially if the test compound was a derivative of the reference compound. When developing new assays or protocols, compounds according to the present invention could be used to test their effectiveness.

[0269] The compounds of the present invention may also be used in diagnostic assays involving factor Xa. For example, the presence of factor Xa in an unknown sample could be determined by addition of chromogenic substrate S2222 to a series of solutions containing test sample and optionally one of the compounds of the present invention. If production of pNA is observed in the solutions containing test sample, but not in the presence of a compound of the present invention, then one would conclude factor Xa was present.

Dosage and Formulation

[0270] The compounds of this invention can be administered in such oral dosage forms as tablets, capsules (each of which includes sustained release or timed release formulations), pills, powders, granules, elixirs, tinctures, suspensions, syrups, and emulsions. They may also be administered in intravenous (bolus or infusion), intraperitoneal, subcutaneous, or intramuscular form, all using dosage forms well known to those of ordinary skill in the pharmaceutical arts. They can be administered alone, but generally will be administered with a pharmaceutical carrier selected on the basis of the chosen route of administration and standard pharmaceutical practice.

[0271] The dosage regimen for the compounds of the present invention will, of course, vary depending upon known factors, such as the pharmacodynamic characteristics of the particular agent and its mode and route of administration; the species, age, sex, health, medical condition, and weight of the recipient; the nature and extent of the symptoms; the kind of concurrent treatment; the frequency of treatment; the route of administration, the renal and hepatic function of the patient, and the effect desired. A physician or veterinarian can determine and prescribe the effective amount of the drug required to prevent, counter, or arrest the progress of the thromboembolic disorder.

[0272] By way of general guidance, the daily oral dosage of each active ingredient, when used for the indicated effects, will range between about 0.001 to 1000 mg/kg of body weight, preferably between about 0.01 to 100 mg/kg of body weight per day, and most preferably between about 1.0 to 20 mg/kg/day. Intravenously, the most preferred doses will range from about 1 to about 10 mg/kg/minute during a constant rate infusion. Compounds of this invention may be administered in a single daily dose, or the total daily dosage may be administered in divided doses of two, three, or four times daily.

[0273] Compounds of this invention can be administered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal routes, using transdermal skin patches. When administered in the form of a transdermal delivery system, the dosage administration will, of course, be continuous rather than intermittent throughout the dosage regimen.

[0274] The compounds are typically administered in admixture with suitable pharmaceutical diluents, excipients, or carriers (collectively referred to herein as pharmaceutical carriers) suitably selected with respect to the intended form of administration, that is, oral tablets, capsules, elixirs, syrups and the like, and consistent with conventional pharmaceutical practices.

[0275] For instance, for oral administration in the form of a tablet or capsule, the active drug component can be combined with an oral, non-toxic, pharmaceutically acceptable, inert carrier such as lactose, starch, sucrose, glucose, methyl callulose, magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, sorbitol and the like; for oral administration in liquid form, the oral drug components can be combined with any oral, non-toxic, pharmaceutically acceptable inert carrier such as ethanol, glycerol, water, and the like. Moreover, when desired or necessary, suitable binders, lubricants, disintegrating agents, and coloring agents can also be incorporated into the mixture. Suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth, or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes, and the like. Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, and the like. Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum, and the like.

[0276] The compounds of the present invention can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles, and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine, or phosphatidylcholines.

[0277] Compounds of the present invention may also be coupled with soluble polymers as targetable drug carriers. Such polymers can include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamide-phenol, polyhydroxyethylaspartamidephenol, or polyethyleneoxide-polylysine substituted with palmitoyl residues. Furthermore, the compounds of the present invention may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacylates, and crosslinked or amphipathic block copolymers of hydrogels.

[0278] Dosage forms (pharmaceutical compositions) suitable for administration may contain from about 1 milligram to about 100 milligrams of active ingredient per dosage unit. In these pharmaceutical compositions the active ingredient will ordinarily be present in an amount of about 0.5-95% by weight based on the total weight of the composition.

[0279] Gelatin capsules may contain the active ingredient and powdered carriers, such as lactose, starch, cellulose derivatives, magnesium stearate, stearic acid, and the like. Similar diluents can be used to make compressed tablets. Both tablets and capsules can be manufactured as sustained release products to provide for continuous release of medication over a period of hours. Compressed tablets can be sugar coated or film coated to mask any unpleasant taste and protect the tablet from the atmosphere, or enteric coated for selective disintegration in the gastrointestinal tract.

[0280] Liquid dosage forms for oral administration can contain coloring and flavoring to increase patient acceptance.

[0281] In general, water, a suitable oil, saline, aqueous dextrose (glucose), and related sugar solutions and glycols such as propylene glycol or polyethylene glycols are suitable carriers for parenteral solutions. Solutions for parenteral administration preferably contain a water soluble salt of the active ingredient, suitable stabilizing agents, and if necessary, buffer substances. Antioxidizing agents such as sodium bisulfite, sodium sulfite, or ascorbic acid, either alone or combined, are suitable stabilizing agents. Also used are citric acid and its salts and sodium EDTA. In addition, parenteral solutions can contain preservatives, such as benzalkonium chloride, methyl- or propyl-paraben, and chlorobutanol.

[0282] Suitable pharmaceutical carriers are described in Remington's Pharmaceutical Sciences, Mack Publishing Company, a standard reference text in this field.

[0283] Representative useful pharmaceutical dosage-forms for administration of the compounds of this invention can be illustrated as follows:

[0284] Capsules

[0285] A large number of unit capsules can be prepared by filling standard two-piece hard gelatin capsules each with 100 milligrams of powdered active ingredient, 150 milligrams of lactose, 50 milligrams of cellulose, and 6 milligrams magnesium stearate.

[0286] Soft Gelatin Capsules

[0287] A mixture of active ingredient in a digestable oil such as soybean oil, cottonseed oil or olive oil may be prepared and injected by means of a positive displacement pump into gelatin to form soft gelatin capsules containing 100 milligrams of the active ingredient. The capsules should be washed and dried.

[0288] Tablets

[0289] Tablets may be prepared by conventional procedures so that the dosage unit is 100 milligrams of active ingredient, 0.2 milligrams of colloidal silicon dioxide, 5 milligrams of magnesium stearate, 275 milligrams of microcrystalline cellulose, 11 milligrams of starch and 98.8 milligrams of lactose. Appropriate coatings may be applied to increase palatability or delay absorption.

[0290] Injectable

[0291] A parenteral composition suitable for administration by injection may be prepared by stirring 1.5% by weight of active ingredient in 10% by volume propylene glycol and water. The solution should be made isotonic with sodium chloride and sterilized.

[0292] Suspension

[0293] An aqueous suspension can be prepared for oral administration so that each 5 mL contain 100 mg of finely divided active ingredient, 200 mg of sodium carboxymethyl cellulose, 5 mg of sodium benzoate, 1.0 g of sorbitol solution, U.S.P., and 0.025 mL of vanillin.

[0294] Where the compounds of this invention are combined with other anticoagulant agents, for example, a daily dosage may be about 0.1 to 100 milligrams of the compound of Formula I and about 1 to 7.5 milligrams of the second anticoagulant, per kilogram of patient body weight. For a tablet dosage form, the compounds of this invention generally may be present in an amount of about 5 to 10 milligrams per dosage unit, and the second anti-coagulant in an amount of about 1 to 5 milligrams per dosage unit.

[0295] Where the compounds of Formula I are administered in combination with an anti-platelet agent, by way of general guidance, typically a daily dosage may be about 0.01 to 25 milligrams of the compound of Formula I and about 50 to 150 milligrams of the anti-platelet agent, preferably about 0.1 to 1 milligrams of the compound of Formula I and about 1 to 3 milligrams of antiplatelet agents, per kilogram of patient body weight.

[0296] Where the compounds of Formula I are adminstered in combination with thrombolytic agent, typically a daily dosage may be about 0.1 to 1 milligrams of the compound of Formula I, per kilogram of patient body weight and, in the case of the thrombolytic agents, the usual dosage of the thrombolyic agent when administered alone may be reduced by about 70-80% when administered with a compound of Formula I.

[0297] Where two or more of the foregoing second therapeutic agents are administered with the compound of Formula I, generally the amount of each component in a typical daily dosage and typical dosage form may be reduced relative to the usual dosage of the agent when administered alone, in view of the additive or synergistic effect of the therapeutic agents when administered in combination.

[0298] Particularly when provided as a single dosage unit, the potential exists for a chemical interaction between the combined active ingredients. For this reason, when the compound of Formula I and a second therapeutic agent are combined in a single dosage unit they are formulated such that although the active ingredients are combined in a single dosage unit, the physical contact between the active ingredients is minimized (that is, reduced). For example, one active ingredient may be enteric coated. By enteric coating one of the active ingredients, it is possible not only to minimize the contact between the combined active ingredients, but also, it is possible to control the release of one of these components in the gastrointestinal tract such that one of these components is not released in the stomach but rather is released in the intestines. One of the active ingredients may also be coated with a material which effects a sustained-release throughout the gastrointestinal tract and also serves to minimize physical contact between the combined active ingredients. Furthermore, the sustained-released component can be additionally enteric coated such that the release of this component occurs only in the intestine. Still another approach would involve the formulation of a combination product in which the one component is coated with a sustained and/or enteric release polymer, and the other component is also coated with a polymer such as a lowviscosity grade of hydroxypropyl methylcellulose (HPMC) or other appropriate materials as known in the art, in order to further separate the active components. The polymer coating serves to form an additional barrier to interaction with the other component.

[0299] These as well as other ways of minimizing contact between the components of combination products of the present invention, whether administered in a single dosage form or administered in separate forms but at the same time by the same manner, will be readily apparent to those skilled in the art, once armed with the present disclosure.

[0300] Obviously, numerous modifications and variations of the present invention are possible in light of the above teachings. It is therefore to be understood that within the scope of the appended claims, the invention may be practiced otherwise that as specifically described herein. 

What is claimed is;
 1. A compound of formula I:

or a stereoisomer or pharmaceutically acceptable salt thereof, wherein; M¹ is N or CR^(1c); M² is NR^(1a) or CR^(1a)R^(1a), provided that only one of M¹ and M² is a N atom; D is selected from C(═NR⁸)NR⁷R⁹, NHC(═NR⁸)NR⁷R⁹, NR⁸CH(═NR⁷), C(O)NR⁷R⁸, and CR⁸R⁹NR⁷R⁸; E is selected from phenyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, and piperidinyl substituted with 1 R; alternatively, D—E—G together represent pyridyl substituted with 1 R; R is selected from H, Cl, F, Br, I, (CH₂)_(t)OR³, C₁₋₄ alkyl, OCF₃, CF₃, C(O)NR⁷R⁸, and (CR⁸R⁹)_(t)NR⁷R⁸; G is selected from NHCH₂, OCH₂, and SCH₂, provided that when s is 0, then G is absent; Z is selected from a C₁₋₄ alkylene, (CH₂)_(r)O(CH₂)_(r), (CH₂)_(r)NR³(CH₂)_(r), (CH₂)_(r)C(O)(CH₂)_(r), (CH₂)_(r)C(O)O(CH₂)_(r), (CH₂)_(r)OC(O)(CH₂)_(r), (CH₂)_(r)C(O)NR³(CH₂)_(r), (CH₂)_(r)NR³C(O)(CH₂)_(r), (CH₂)_(r)OC(O)O(CH₂)_(r), (CH₂)_(r)OC(O)NR³(CH₂)_(r), (CH₂)_(r)NR³C(O)O(CH₂)_(r), (CH₂)_(r)NR³C(O)NR³(CH₂)_(r), (CH₂)_(r)S(O)_(p)(CH₂)_(r), (CH₂)_(r)SO₂NR³(CH₂)_(r), (CH₂)_(r)NR³SO₂(CH₂)_(r), and (CH₂)_(r)NR³SO₂NR³(CH₂)_(r), provided that Z does not form a N—N, N—O, N—S, NCH₂N, NCH₂O, or NCH₂S bond with group A; R^(1a) and R^(1b) are, at each occurrence, independently selected from H, —(CH₂)_(r)—R¹′, NCH₂R¹″, OCH₂R¹, SCH₂R¹, N(CH₂)₂(CH₂)_(t)R¹′, O(CH₂)₂(CH₂)_(t)R¹′, and S(CH₂)₂(CH₂)_(t)R¹′; R^(1c) is selected from H, —(CH₂)_(q)—R¹′, C₁₋₃ alkyl, C(O)R^(2c), (CF₂)_(r)CO₂R^(2c), C(O)NR²R^(2a), C₃₋₆ carbocyclic residue substituted with 0-2 R⁴, and 5-10 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R⁴; R¹′ is selected from H, C₁₋₃ alkyl, halo, (CF₂)_(r)CF₃, OR², NR²R^(2a), C(O)R^(2c), OC(O)R², (CF₂)_(r)CO₂R^(2c), S(O)_(p)R^(2b), NR²(CH₂)_(r)OR², NR²C(O)R^(2b), NR²C(O)NHR^(2b), NR²C(O)₂R^(2a), OC (₀)NR^(2b), C(O)NR²R^(2a), SO₂NR²R^(2a), NR²SO₂R^(2b), C₃₋₆ carbocyclic residue substituted with 0-2 R⁴, and 5-10 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R⁴; R¹″ is selected from H, C(O)R^(2b), C(O)NR²R^(2a), S(O)R^(2b), S(O)₂R^(2b), and SO₂NR²R^(2a); R², at each occurrence, is selected from H, CF₃, C₁₋₆ alkyl, benzyl, C₃₋₆ carbocyclic residue substituted with 0-2 R^(4b), and 5-6 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R^(4b); R^(2a), at each occurrence, is selected from H, CF₃, C₁₋₆ alkyl, benzyl, C₃₋₆ carbocyclic residue substituted with 0-2 R^(4b), and 5-6 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R^(4b); R^(2b), at each occurrence, is selected from CF₃, C₁₋₄ alkoxy, C₁₋₆ alkyl, benzyl, C₃₋₆ carbocyclic residue substituted with 0-2 R^(4b), and 5-6 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R^(4b); R^(2c), at each occurrence, is selected from CF₃, OH, C₁₋₄ alkoxy, C₁₋₆ alkyl, benzyl, C₃₋₆ carbocyclic residue substituted with 0-2 R^(4b), and 5-6 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R^(4b); alternatively, R² and R^(2a) combine to form a 5 or 6 membered saturated, partially saturated or unsaturated ring substituted with 0-2 R^(4b) which contains from 0-1 additional heteroatoms selected from the group consisting of N, O, and S; R³, at each occurrence, is selected from H, C₁₋₄ alkyl, and phenyl; R^(3a), at each occurrence, is selected from H, C₁₋₄ alkyl, and phenyl; A is selected from: C₃₋₁₀ carbocyclic residue substituted with 0-2 R⁴, and 5-10 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R⁴; B is selected from: X—Y, NR²R^(2a), C(═NR²)NR²R^(2a), NR²C(═NR²)NR²R^(2a), C₃₋₁₀ carbocyclic residue substituted with 0-2 R^(4a), and 5-10 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R^(4a); X is selected from C₁₋₄ alkylene, —CR²(CR²R^(2b))(CH₂)_(t)—, —C(O)—, —C(═NR)—, —CR²(NR¹″R²)—, —CR²(OR²)—, —CR²(SR²)—, —C(O)CR²R^(2a)—, —CR²R^(2a)C (O), —S(O)_(p)—, —S(O)_(p)CR²R^(2a)—, —CR²R^(2a)S(O)_(p)—, —S(O)₂NR²—, —NR²S(O)₂—, —NR²S(O)₂CR²R^(2a)—, —CR²R^(2a)S(O)₂NR²—, —NR²S(O)₂NR²—, —C(O)NR²—, —NR²C(O)—, —C(O)NR²CR²R^(2a)—, —NR²C(O)CR²R^(2a)—, —CR²R^(2a)C(O)NR²—, —CR²R^(2a)NR²C(O)—, —NR²C(O)O—, —OC(O)NR²—, —NR²C(O)NR²—, —NR²—, —NR²CR²R^(2a)—, —CR²R^(2a)NR²—, O, —CR²R^(2a)O—, and —OCR²R^(2a)—; Y is selected from: (CH₂)_(r)NR²R^(2a), provided that X—Y do not form a N—N, O—N, or S—N bond, C₃₋₁₀ carbocyclic residue substituted with 0-2 R^(4a), and 5-10 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R^(4a); R⁴, at each occurrence, is selected from ═O, (CH₂)_(r)OR², halo, C₁₋₄ alkyl, —CN, NO₂, (CH₂)_(r)NR²R^(2a), (CH₂)_(r)C(O)R^(2b), NR²C(O)R^(2b), C(O)NR²R^(2a), NR²C(O)NR²R^(2a), CH(═NR²)NR²R^(2a), NHC (═NR²)NR²R^(2a), SO₂NR²R^(2a), NR²SO₂NR²R^(2a), NR²SO₂—C₁₋₄ alkyl, NR²SO₂R⁵, S(O)_(p)R⁵, (CF₂)_(r)CF₃, NCH₂R¹″, OCH₂R¹″, SCH₂R¹″, N(CH₂)₂(CH₂)_(t)R¹′, O(CH₂)₂(CH₂)_(t)R¹′, and S(CH₂)₂(CH₂)_(t)R¹′, alternatively, one R⁴ is a 5-6 membered aromatic heterocycle containing from 1-4 heteroatoms selected from the group consisting of N, O, and S; R^(4a), at each occurrence, is selected from ═O, (CH₂)_(r)OR², halo, C₁₋₄ alkyl, —CN, NO₂, (CH₂)_(r)NR²R^(2a), (CH₂)_(r)C(O)R^(2b), NR²C(O)R^(2b), C(O)NR²R^(2a), NR²C(O)NR²R^(2a), CH(═NR²)NR²R^(2a), NHC(═NR²)NR²R^(2a), SO₂NR²R^(2a), NR²SO₂NR²R^(2a), NR²SO₂—C₁₋₄ alkyl, NR²SO₂R⁵, S(O)_(p)R⁵, and (CF₂)_(r)CF₃; alternatively, one R⁴a is a 5-6 membered aromatic heterocycle containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-1 R⁵; R^(4b), at each occurrence, is selected from ═O, (CH₂)_(r)OR³, halo, C₁₋₄ alkyl, —CN, NO₂, (CH₂)_(r) NR³R^(3a), (CH₂)_(r)C(O)R³, NR³C(O)R^(3a), C(O)NR³R^(3a), NR³C(O)NR³R^(3a), CH(═NR³)NR³R^(3a), NH³C (═NR³) NR³R^(3a), SO₂NR³R^(3a), NR³SO₂NR³R^(3a), NR³SO₂—C₁₋₄ alkyl, NR³SO₂CF₃, NR³SO₂-phenyl, S(O)_(p)CF₃, S(O)_(p)—C₁₋₄ alkyl, S(O)_(p)-phenyl, and (CF₂)_(r)CF₃; R⁵, at each occurrence, is selected from CF₃, C₁₋₆ alkyl, phenyl substituted with 0-2 R⁶, and benzyl substituted with 0-2 R⁶; R⁶, at each occurrence, is selected from H, OH, (CH₂)_(r)OR², halo, C₁₋₄ alkyl, CN, NO₂, (CH₂)_(r)NR²R^(2a), (CH₂)_(r)C(O)R^(2b), NR²C(O)R^(2b), NR²C(O)NR²R^(2a), CH(═NH)NH₂, NHC(═NH)NH₂, SO₂NR²R^(2a), NR²SO₂NR²R^(2a), and NR²SO₂C₁₋₄ alkyl; R⁷, at each occurrence, is selected from H, OH, C₁₋₆ alkyl, C₁₋₆ alkylcarbonyl, C₁₋₆ alkoxy, C₁₋₄ alkoxycarbonyl, (CH₂)_(n)-phenyl, C₆₋₁₀ aryloxy, C₆₋₁₀ aryloxycarbonyl, C₆₋₁₀ arylmethylcarbonyl, C₁₋₄ alkylcarbonyloxy C₁₋₄ alkoxycarbonyl, C₆₋₁₀ arylcarbonyloxy C₁₋₄ alkoxycarbonyl, C₁₋₆ alkylaminocarbonyl, phenylaminocarbonyl, and phenyl C₁₋₄ alkoxycarbonyl; R⁸, at each occurrence, is selected from H, C₁₋₆ alkyl and (CH₂)_(n)-phenyl; alternatively, R⁷ and R⁸ combine to form a 5 or 6 membered saturated, ring which contains from 0-1 additional heteroatoms selected from the group consisting of N, O, and S; R⁹, at each occurrence, is selected from H, C₁₋₆ alkyl and (CH₂) n-phenyl; n, at each occurrence, is selected from 0, 1, 2, and 3; m, at each occurrence, is selected from 0, 1, and 2; p, at each occurrence, is selected from 0, 1, and 2; q, at each occurrence is selected from 1 and 2; r, at each occurrence, is selected from 0, 1, 2, and 3; s, at each occurrence, is selected from 0, 1, and 2; and, t, at each occurrence, is selected from 0 and
 1. 2. A compound according to claim 1, wherein the compound is of formula Ia or Ib:

wherein; Z is selected from a CH₂O, OCH₂, CH₂NH, NHCH₂, C(O), CH₂C(O), C(O)CH₂, NHC(O), C(O)NH, CH₂S(O)₂, S(O)₂(CH₂), SO₂NH, and NHSO₂, provided that Z does not form a N—N,N—O, NCH₂N, or NCH₂O bond with group A; A is selected from one of the following carbocyclic and heterocyclic systems which are substituted with 0-2 R⁴; phenyl, piperidinyl, piperazinyl, pyridyl, pyrimidyl, furanyl, morpholinyl, thiophenyl, pyrrolyl, pyrrolidinyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, triazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, benzofuranyl, benzothiofuranyl, indolyl, benzimidazolyl, benzoxazolyl, benzthiazolyl, indazolyl, benzisoxazolyl, benzisothiazolyl, and isoindazolyl; B is selected from: Y, X—Y, NR²R^(2a), C(═NR²)NR²R^(2a), and NR²C(═NR²) NR²R^(2a); X is selected from C₁₋₄ alkylene, —C(O)—, —C(═NR)—, —CR²(NR²R^(2a))—, —C(O)CR²R^(2a)—, —CR²R^(2a)C(O), —C(O)NR²—, —NR²C(O)—, —C(O)NR²CR²R^(2a)—, —NR²C(O)CR²R^(2a)—, —CR²R^(2a)C(O)NR²—, —CR²R^(2a)NR²C(O)—, —NR²C(O)NR²—, —NR²—, —NR²CR²R^(2a)—, —CR²R^(2a)NR²—, O, —CR²R^(2a)O—, and —OCR²R^(2a)—; Y is NR²R^(2a), provided that X—Y do not form a N—N or O—N bond; alternatively, Y is selected from one of the following carbocyclic and heterocyclic systems which are substituted with 0-2 R^(4a); cylcopropyl, cyclopentyl, cyclohexyl, phenyl, piperidinyl, piperazinyl, pyridyl, pyrimidyl, furanyl, morpholinyl, thiophenyl, pyrrolyl, pyrrolidinyl, oxazolyl, isoxazolyl, isoxazolinyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, triazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, benzofuranyl, benzothiofuranyl, indolyl, benzimidazolyl, benzoxazolyl, benzthiazolyl, indazolyl, benzisoxazolyl, benzisothiazolyl, and isoindazolyl; alternatively, Y is selected from the following bicyclic heteroaryl ring systems:

K is selected from O, S, NH, and N.
 3. A compound according to claim 2, wherein; Z is selected from a C(O), CH₂C(O), C(O)CH₂, NHC(O), C(O)NH, C(O)N(CH₃), CH₂S(O)₂, S(O)₂ (CH₂), SO₂NH, and NHSO₂, provided that Z does not form a N—N or NCH₂N bond with group A.
 4. A compound according to claim 3, wherein; E is phenyl substituted with R or 2-pyridyl substituted with R; D is selected from C(O)NH₂, C(═NH)NH₂, CH₂NH₂, CH₂NHCH₃, CH(CH₃)NH₂, and C(CH₃)₂NH₂; and, R is selected from H, OCH₃, Cl, and F.
 5. A compound according to claim 4, wherein; D—E is selected from 3-amidinophenyl, 3-aminomethylphenyl, 3-aminocarbonylphenyl, 3-(methylaminomethyl)phenyl, 3-(1-aminoethyl)phenyl, 3-(2-amino-2-propyl)phenyl, 4-chloro-3-amidinophenyl, 4-chloro-3-aminomethylphenyl, 4-chloro-3-(methylaminomethyl)phenyl, 4-fluoro-3-amidinophenyl, 4-fluoro-3-aminomethylphenyl, 4-fluoro-3-(methylaminomethyl)phenyl, 6-amidinopyrid-2-yl, 6-aminomethylpyrid-2-yl, 6-aminocarbonylpyrid-2-yl, 6-(methylaminomethyl)pyrid-2-yl, 6-(1-aminoethyl)pyrid-2-yl, and 6-(2-amino-2-propyl)pyrid-2-yl.
 6. A compound according to claim 3, wherein; Z is C(O)CH₂ and CONH, provided that Z does not form a N—N bond with group A; A is selected from phenyl, pyridyl, and pyrimidyl, and is substituted with 0-2 R⁴; and, B is selected from X—Y, phenyl, pyrrolidino, morpholino, 1,2,3-triazolyl, and imidazolyl, and is substituted with 0-1 R^(4a); R⁴, at each occurrence, is selected from OH, (CH₂)_(r)OR², halo, C₁₋₄ alkyl, (CH₂)_(r)NR²R^(2a), and (CF₂)_(r)CF₃; R^(4a) is selected from C₁₋₄ alkyl, CF₃, S(O)_(p)R⁵, SO₂NR²R^(2a), and 1-CF₃-tetrazol-2-yl; R⁵, at each occurrence, is selected from CF₃, C₁₋₆ alkyl, phenyl, and benzyl; X is CH₂ or C(O); and, Y is selected from pyrrolidino and morpholino.
 7. A compound according to claim 6, wherein; A is selected from the group: phenyl, 2-pyridyl, 3-pyridyl, 2-pyrimidyl, 2-Cl-phenyl, 3-Cl-phenyl, 2-F-phenyl, 3-F-phenyl, 2-methylphenyl, 2-aminophenyl, and 2-methoxyphenyl; and, B is selected from the group: 2-CF₃-phenyl, 2-(aminosulfonyl)phenyl, 2-(methylaminosulfonyl)phenyl, 2-(dimethylaminosulfonyl)phenyl, 1-pyrrolidinocarbonyl, 2-(methylsulfonyl)phenyl, 4-morpholino, 2-(1′-CF₃-tetrazol-2-yl)phenyl, 4-morpholinocarbonyl, 2-methyl-1-imidazolyl, 5-methyl-1-imidazolyl, 2-methylsulfonyl-1-imidazolyl and, 5-methyl-1,2,3-triazolyl.
 8. A compound according to claim 3, wherein; E is phenyl substituted with R or 2-pyridyl substituted with R; D is selected from C(O)NH₂, C(═NH)NH₂, CH₂NH₂, CH₂NHCH₃, CH(CH₃)NH₂, and C(CH₃)₂NH₂; and, R is selected from H, OCH₃, Cl, and F; Z is C(O)CH₂ and CONH, provided that Z does not form a N—N bond with group A; A is selected from phenyl, pyridyl, and pyrimidyl, and is substituted with 0-2 R⁴; and, B is selected from X—Y, phenyl, pyrrolidino, morpholino, 1,2,3-triazolyl, and imidazolyl, and is substituted with 0-1 R^(4a); R⁴, at each occurrence, is selected from OH, (CH₂)_(r)OR², halo, C₁₋₄ alkyl, (CH₂)_(r)NR²R^(2a), and (CF₂)_(r)CF₃; R^(4a) is selected from C₁₋₄ alkyl, CF₃, S(O)_(p)R⁵, SO₂NR²R^(2a), and 1-CF₃-tetrazol-2-yl; R⁵, at each occurrence, is selected from CF₃, C₁₋₆ alkyl, phenyl, and benzyl; X is CH₂ or C(O); and, Y is selected from pyrrolidino and morpholino.
 9. A compound according to claim 8 wherein; D—E is selected from 3-amidinophenyl, 3-aminomethylphenyl, 3-aminocarbonylphenyl, 3-(methylaminomethyl)phenyl, 3-(1-aminoethyl)phenyl, 3-(2-amino-2-propyl)phenyl, 4-chloro-3-amidinophenyl, 4-chloro-3-aminomethylphenyl, 4-chloro-3-(methylaminomethyl)phenyl, 4-fluoro-3-amidinophenyl, 4-fluoro-3-aminomethylphenyl, 4-fluoro-3-(methylaminomethyl)phenyl, 6-amidinopyrid-2-yl, 6-aminomethylpyrid-2-yl, 6-aminocarbonylpyrid-2-yl, 6-(methylaminomethyl)pyrid-2-yl, 6-(1-aminoethyl)pyrid-2-yl, 6-(2-amino-2-propyl)pyrid-2-yl; A is selected from the group: phenyl, 2-pyridyl, 3-pyridyl, 2-pyrimidyl, 2-Cl-phenyl, 3-Cl-phenyl, 2-F-phenyl, 3-F-phenyl, 2-methylphenyl, 2-aminophenyl, and 2-methoxyphenyl; and, B is selected from the group: 2-CF₃-phenyl, 2-(aminosulfonyl)phenyl, 2-(methylaminosulfonyl)phenyl, 2-(dimethylaminosulfonyl)phenyl, 1-pyrrolidinocarbonyl, 2-(methylsulfonyl)phenyl, 4-morpholino, 2-(1′-CF₃-tetrazol-2-yl)phenyl, 4-morpholinocarbonyl, 2-methyl-1-imidazolyl, 5-methyl-1-imidazolyl, 2-methylsulfonyl-1-imidazolyl and, 5-methyl-1,2,3-triazolyl.
 10. A compound according to claim 9, wherein the compound is of formula Ia.
 11. A compound according to claim 9, wherein the compound is of formula Ib.
 12. A compound according to claim 3, wherein; D is selected from C(═NR⁸)NR⁷R⁹, C(O)NR⁷R⁸, NR⁷R⁸, and CH₂NR⁷R⁸; E is phenyl substituted with R or pyridyl substituted with R; R is selected from H, Cl, F, OR³, CH₃, CH₂CH₃, OCF₃, and CF₃; Z is selected from C(O), CH₂C(O), C(O)CH₂, NHC(O), and C(O)NH, provided that Z does not form a N—N bond with group A; R^(1a) and R^(1b) are, at each occurrence, independently selected from H, —(CH₂)_(r)—R¹′, NCH₂R¹, OCH₂R¹, SCH₂R¹, N(CH₂) 2(CH₂)_(t)R¹′, O(CH₂)₂(CH₂)_(t)R¹′, and S(CH₂)₂(CH₂)_(t)R¹′; R^(1c) is selected from H, —(CH₂)_(q)—R¹′, C₁₋₃ alkyl, C(O)R^(2c), (CF₂)_(r)CO₂R^(2c), and C(O)NR²R^(2a); R¹′, at each occurrence, is selected from H, C₁₋₃ alkyl, halo, (CF₂)_(r)CF₃, OR², NR²R^(2a), C(O)R^(2c), (CF₂)_(r)CO₂R^(2c), S(O)_(p)R^(2b), NR²(CH₂)_(r)OR², NR²C(O)R^(2b), NR²C(°)₂R^(2b), C(O)NR²R^(2a), SO₂NR²R^(2a), and NR²SO₂R^(2b); A is selected from one of the following carbocyclic and heterocyclic systems which are substituted with 0-2 R⁴; phenyl, piperidinyl, piperazinyl, pyridyl, pyrimidyl, furanyl, morpholinyl, thiophenyl, pyrrolyl, pyrrolidinyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, and imidazolyl; B is selected from: Y, X—Y, NR²R^(2a), C(═NR²)NR²R^(2a), and NR²C(═NR²) NR²R^(2a); X is selected from CH₂, —CR²(CR²R^(2b))(CH₂)_(t)—, —C(O)—, —C(═NR)—, —CH(NR²R^(2a))—, —C(O)NR²—, —NR²C(O)—, —NR²C(O)NR²—, —NR²—, and O; Y is NR²R^(2a), provided that X—Y do not form a N—N or O—N bond; alternatively, Y is selected from one of the following carbocyclic and heterocyclic systems which are substituted with 0-2 R^(4a); phenyl, piperidinyl, piperazinyl, pyridyl, pyrimidyl, furanyl, morpholinyl, thiophenyl, pyrrolyl, pyrrolidinyl, oxazolyl, isoxazolyl, isoxazolinyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, triazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, and 1,3,4-triazolyl; R⁴, at each occurrence, is selected from ═O, OH, Cl, F, C₁₋₄ alkyl, (CH₂)_(r)NR²R^(2a), (CH₂)_(r)C(O)R^(2b), NR²C(O)R^(2b), C(O)NR²R^(2a), CH(═NH)NH₂, NHC(═NH)NH₂, SO₂NR²R^(2a), NR²SO₂—C₁₋₄ alkyl, NR²SO₂R⁵, S(O)_(p)R⁵, and (CF₂)_(r)CF₃; R^(4a), at each occurrence, is selected from ═O, OH, Cl, F, C₁₋₄ alkyl, (CH₂)_(r)NR²R^(2a), (CH₂)_(r)C(O)R^(2b), NR²C(O)R^(2b), C(O)NR²R^(2a), CH(═NH)NH₂, NHC(═NH)NH₂, SO₂NR²R^(2a), NR²SO₂—C₁₋₄ alkyl, NR²SO₂R⁵, S(O)_(p)R⁵, (CF₂)_(r)CF₃, and 1-CF₃-tetrazol-2-yl; R⁵, at each occurrence, is selected from CF₃, C₁₋₆ alkyl, phenyl substituted with 0-2 R⁶, and benzyl substituted with 0-2 R⁶; R⁶, at each occurrence, is selected from H, ═O, OH, OR², Cl, F, CH₃, CN, NO₂, (CH₂)_(r)NR²R^(2a), (CH₂)_(r)C(O)R^(2b), NR²C(O)R^(2b), CH(═NH)NH₂, NHC(═NH)NH₂, and SO₂NR²R^(2a); R⁷, at each occurrence, is selected from H, OH, C₁₋₆ alkyl, C₁₋₆ alkylcarbonyl, C₁₋₆ alkoxy, C₁₋₄ alkoxycarbonyl, benzyl, C₆₋₁₀ aryloxy, C₆₋₁₀ aryloxycarbonyl, C₆₋₁₀ arylmethylcarbonyl, C₁₋₄ alkylcarbonyloxy C₁₋₄ alkoxycarbonyl, C₆₋₁₀ arylcarbonyloxy C₁₋₄ alkoxycarbonyl, C₁₋₆ alkylaminocarbonyl, phenylaminocarbonyl, and phenyl C₁₋₄ alkoxycarbonyl; R⁸, at each occurrence, is selected from H, C₁₋₆ alkyl and benzyl; and alternatively, R⁷ and R⁸ combine to form a morpholino group; and, R⁹, at each occurrence, is selected from H, C₁₋₆ alkyl and benzyl.
 13. A compound according to claim 12, wherein; E is phenyl substituted with R or 2-pyridyl substituted with R; R is selected from H, Cl, F, OCH₃, CH₃, OCF₃, and CF₃; Z is selected from a C(O)CH₂ and C(O)NH, provided that Z does not form a N—N bond with group A; R¹a, at each occurrence, is selected from H, CH₃, CH₂CH₃, Cl, F, CF₃, OCH₃, NR²R^(2a), S(O)_(p)R^(2b), CH₂S(O)_(p)R^(2b), CH₂NR²S(O)_(p)R^(2b), C(O)R^(2c), CH₂C(O)R^(2c), C(O)NR²R^(2a), and SO₂NR²R^(2a); R^(1b) is selected from H, CH₃, CH₂CH₃, Cl, F, CF₃, OCH₃, NR²R^(2a), S(O)_(p)R^(2b), CH₂S(O)_(p)R^(2b), CH₂NR²S(O)_(p)R^(2b), C(O)R^(2c), CH₂C(O)R^(2c), C(O)NR²R^(2a), and SO₂NR²R^(2a); R^(1c) is selected from H, CH₃, CH₂CH₃, CF₃, CH₂S(O)_(p)R^(2b), CH₂NR²S(O)_(p)R^(2b), C(O)R^(2c), CH₂C(O)R^(2c), and C(O)NR²R^(2a); A is selected from one of the following carbocyclic and heterocyclic systems which are substituted with 0-2 R⁴; phenyl, pyridyl, pyrimidyl, furanyl, thiophenyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, and imidazolyl; B is selected from: Y and X—Y; X is selected from CH₂, —CR²(CR²R^(2b))—, —C(O)—, —C(═NR)—, —CH(NR²R^(2a))—, —C(O)NR²—, —NR²C(O)—, —NR²C(O)NR²—, —NR²—, and O; Y is NR²R^(2a), provided that X—Y do not form a N—N or O—N bond; alternatively, Y is selected from one of the following carbocyclic and heterocyclic systems which are substituted with 0-2 R^(4a); phenyl, piperidinyl, piperazinyl, pyridyl, pyrimidyl, furanyl, morpholinyl, thiophenyl, pyrrolyl, pyrrolidinyl, oxazolyl, isoxazolyl, isoxazolinyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, triazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, and 1,3,4-triazolyl; R², at each occurrence, is selected from H, CF₃, CH₃, benzyl, and phenyl; R^(2a), at each occurrence, is selected from H, CF₃, CH₃, benzyl, and phenyl; R^(2b), at each occurrence, is selected from CF₃, OCH₃, CH₃, benzyl, and phenyl; R^(2c), at each occurrence, is selected from CF₃, OH, OCH₃, CH₃, benzyl, and phenyl; alternatively, R² and R^(2a) combine to form a 5 or 6 membered saturated, partially unsaturated, or unsaturated ring which contains from 0-1 additional heteroatoms selected from the group consisting of N, O, and S; R³, at each occurrence, is selected from H, CH₃, CH₂CH₃, and phenyl; R^(3a), at each occurrence, is selected from H, CH₃, CH₂CH₃, and phenyl; R⁴, at each occurrence, is selected from OH, Cl, F, CH₃, CH₂CH₃, NR²R^(2a), CH₂NR²R^(2a), C(O)R^(2b), NR²C(O)R^(2b), C(O)NR²R^(2a), and CF₃; R^(4a), at each occurrence, is selected from OH, Cl, F, CH₃, CH₂CH₃, NR²R^(2a), CH₂NR²R^(2a), C(O)R^(2b), C(O)NR²R^(2a), SO₂NR²R^(2a), S(O)_(p)R⁵, CF₃, and 1-CF₃-tetrazol-2-yl; R⁵, at each occurrence, is selected from CF₃, C₁₋₆ alkyl, phenyl substituted with 0-2 R⁶, and benzyl substituted with 1 R⁶; R⁶, at each occurrence, is selected from H, OH, OCH₃, Cl, F, CH₃, CN, NO₂, NR²R^(2a), CH₂NR²R^(2a), and SO₂NR²R^(2a); R⁷, at each occurrence, is selected from H, OH, C₁₋₃ alkyl, C₁₋₃ alkylcarbonyl, C₁₋₃ alkoxy, C₁₋₄ alkoxycarbonyl, benzyl, phenoxy, phenoxycarbonyl, benzylcarbonyl, C₁₋₄ alkylcarbonyloxy C₁₋₄ alkoxycarbonyl, phenylcarbonyloxy C₁₋₄ alkoxycarbonyl, C₁₋₆ alkylaminocarbonyl, phenylaminocarbonyl, and phenyl C₁₋₄ alkoxycarbonyl; R⁸, at each occurrence, is selected from H, CH₃, and benzyl; and, alternatively, R⁷ and R⁸ combine to form a morpholino group; R⁹, at each occurrence, is selected from H, CH₃, and benzyl.
 14. A compound according to claim 13, wherein; R^(1a), at each occurrence, is selected from H, CH₃, CH₂CH₃, Cl, F, CF₃, OCH₃, NR²R^(2a), S(O)_(p)R^(2b), C(O)NR²R^(2a), CH₂S(O)_(p)R^(2b), CH₂NR²S(O)_(p)R^(2b), C(O)R^(2c), CH₂C(O)R^(2c), and SO₂NR²R^(2a); R^(1b) is selected from H, CH₃, CH₂CH₃, Cl, F, CF₃, OCH₃, NR²R^(2a), S(O)_(p)R^(2b), C(O)NR²R^(2a), CH₂S(O)_(p)R^(2b), CH₂NR²S(O)_(p)R^(2b), C(O)R^(2b), CH₂C(O)R^(2b), and SO₂NR²R^(2a); R^(1c) is selected from H, CH₃, CH₂CH₃, CF₃, C(O)NR²R^(2a), CH₂S(O)_(p)R^(2b), CH₂NR²S(O)_(p)R^(2b), C(O)R^(2b), and CH₂C(O)R^(2b); A is selected from one of the following carbocyclic and heterocyclic systems which are substituted with 0-2 R⁴; phenyl, pyridyl, and pyrimidyl; B is selected from: Y and X—Y; X is selected from —C(O)— and O; Y is NR²R^(2a), provided that X—Y do not form a O—N bond; alternatively, Y is selected from one of the following carbocyclic and heterocyclic systems which are substituted with 0-2 R^(4a); phenyl, piperazinyl, pyridyl, pyrimidyl, morpholinyl, pyrrolidinyl, imidazolyl, and 1,2,3-triazolyl; R², at each occurrence, is selected from H, CF₃, CH₃, benzyl, and phenyl; R^(2a), at each occurrence, is selected from H, CF₃, CH₃, benzyl, and phenyl; R^(2b), at each occurrence, is selected from CF₃, OCH₃, CH₃, benzyl, and phenyl; R^(2c), at each occurrence, is selected from CF₃, OH, OCH₃, CH₃, benzyl, and phenyl; alternatively, R² and R^(2a) combine to form a ring system selected from pyrrolidinyl, piperazinyl and morpholino; R⁴, at each occurrence, is selected from Cl, F, CH₃, NR²R^(2a), and CF₃; R^(4a), at each occurrence, is selected from Cl, F, CH₃, SO₂NR²R^(2a), S(O)_(p)R⁵, and CF₃; and, R⁵, at each occurrence, is selected from CF₃ and CH₃.
 15. A compound according to claim 1, wherein the compound is selected from the group: 1-(3-amidinophenyl)-5-[[(2′-methylsulfonyl-[1,1′]-biphen-4-yl)-aminocarbonyl]-3-trifluoromethyl-pyrazoline; and, 1-(3-aminomethylphenyl)-5-[[(2′-methylsulfonyl-[1,1′]-biphen-4-yl)-aminocarbonyl]-3-trifluoromethyl-pyrazoline; and pharmaceutically acceptable salts thereof.
 16. A pharmaceutical composition, comprising: a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound according to claim 1 or a pharmaceutically acceptable salt thereof.
 17. A method for treating or preventing a thromboembolic disorder, comprising: administering to a patient in need thereof a therapeutically effective amount of a compound according to claim 1 or a pharmaceutically acceptable salt thereof. 